Protein-targeting compounds and pharmaceutical compositions thereof, and their therapeutic applications

ABSTRACT

The present disclosure provides compounds, for example, a compound of Formula (I), that modulate a protein function and/or restore protein homeostasis. The disclosure provides a method of modulating a protein-mediated disease, disorder, condition, or response. Compositions, including in combination with other therapeutic agents, are provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 16/882,750, filed May 26, 2020; which claims the benefit U.S.Provisional Application No. 62/852,844, filed May 24, 2019; thedisclosure of each of which is incorporated herein by reference in itsentirety.

FIELD

The present disclosure provides compounds that modulate a proteinfunction and/or restore protein homeostasis. The disclosure provides amethod of modulating a protein-mediated disease, disorder, condition, orresponse. Compositions, including in combination with other therapeuticagents, are provided.

BACKGROUND

Aberrant protein function, and/or protein imbalance is a hallmark ofmany disease states. For example, the functioning of the immune systemis finely balanced by the activities of pro-inflammatory andanti-inflammatory mediators or cytokines. Some cytokines promoteinflammation (pro-inflammatory cytokines), whereas other cytokinessuppress the activity of the pro-inflammatory cytokines(anti-inflammatory cytokines). For example, IL-4, IL-10, and IL-13 arepotent activators of B lymphocytes, and also act as anti-inflammatoryagents. They are anti-inflammatory cytokines by virtue of their abilityto suppress genes for pro-inflammatory cytokines such as IL-1, TNF, andchemokines.

Unregulated activities of these mediators can lead to the development ofserious inflammatory conditions. For example, autoimmune diseases arisewhen immune system cells (lymphocytes, macrophages) become sensitizedagainst the “self.” Lymphocytes, as well as macrophages, are usuallyunder control in this system. However, a misdirection of the systemtoward the body's own tissues may happen in response to stillunexplained triggers. One hypothesis is that lymphocytes recognize anantigen which mimics the “self” and a cascade of activation of differentcomponents of the immune system takes place, ultimately leading totissue destruction. Genetic predisposition has also been postulated tobe responsible for autoimmune disorders.

Misregulation of protein synthesis may contribute to uncontrolled cellgrowth, proliferation, and migration, leading to cancer. For example,the translation termination factor GSPT1 (eRF3a) mediates stop codonrecognition and facilitates release of a nascent peptide from theribosome. In addition to its role in translation termination, GSPT1 isalso involved in several other critical cellular processes, such as cellcycle regulation, cytoskeleton organization, and apoptosis. GSPT1 hasbeen implicated as an oncogenic driver of several different cancertypes, including breast cancer, hepatocellular carcinoma, gastriccancer, and prostate cancer. Brito et al., Carcinogenesis, 26:2046-9(2005); Malta-Vacas et al., Cancer Genet. Cytogenet., 195:132-42 (2009);Miri et al., Med. Oncol., 29:1581-5 (2011); Wright and Lange, Rev.Urol., 9:207-13 (2007); Hashimoto et al., Apoptosis, 17:1287-99 (2012);Liu et. al., PLOS One, 9:e86371 (2014); and Chauvin et al., Mol. Cell.Biol., 27: 5619-29 (2007). GSPT1 also contributes to glial scarformation and astrogliosis after a central nervous system (CNS) injury.Ishii et al., J. Biol. Chem., 292:1240-50 (2017).

Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) arepro-inflammatory cytokines that mediate inflammatory responsesassociated with infectious agents and other cellular stresses.Overproduction of these cytokines is believed to underlie theprogression of many inflammatory diseases, including rheumatoidarthritis (RA), Crohn's disease, inflammatory bowel disease, multiplesclerosis, endotoxin shock, osteoporosis, Alzheimer's disease,congestive heart failure, and psoriasis.

TNF-alpha is produced by a variety of activated immune cells,particularly monocytes and macrophages. Elevated levels of TNF-alphahave been implicated in several pathological conditions, includinginflammation, infection, autoimmune disease, and cancer development.Indeed, virtually all of the players in the human immune system havebeen reported to have some level of functional relationship withTNF-alpha. Wallach, Cytokine, 63:225-9 (2013). TNF-alpha is able toinduce fever, apoptotic cell death, cachexia, inflammation, and toinhibit tumorigenesis and viral replication.

IL-1α and IL-1β are proinflammatory cytokines that activate cells bybinding the IL-1 receptor type I (IL-1RI). These proteins are the mostpowerful endogenous pyrogens known. IL-1α is constitutively expressed asa precursor in cells forming biological barriers, such as epithelialcells, keratinocytes, and mucosal and endothelial cells. IL-1α does notrequire processing for activation and is released from damaged or dyingcells. In contrast, IL-1β must be proteolytically cleaved into itsactive form. Active IL-1β is primarily generated in a subset of bloodmonocytes, dendritic cells, and tissue macrophages, where its activationand release are tightly regulated, although studies systematicallyassessing other cells capable of producing IL-1β are limited. Netea etal., Blood, 113:2324-35 (2009).

Recent data from clinical trials support the use of protein antagonistsof cytokines, for example, a soluble TNF-alpha receptor fusion protein(etanercept) or a monoclonal TNF-alpha antibody (infliximab), for thetreatment of rheumatoid arthritis, Crohn's disease, juvenile chronicarthritis, and psoriatic arthritis. Thus, the reduction ofpro-inflammatory cytokines such as TNF-alpha and interleukin-1 (IL-I)has become an accepted therapeutic approach for potential drugintervention in these conditions.

Moreover, IL-2 is now FDA approved for the treatment of renal cancer andmelanoma, with durable, complete remissions achieved with IL-2 up to 148months. However, the short half-life of IL-2 in serum requires a largeamount of IL-2 to be injected to achieve therapeutic levels. Manyattempts have been made to minimize side effects of systemic IL-2treatment, for example, introducing IL-2 directly into the tumor, thoughthis complicates treatment, and has largely been unsuccessful.

Local delivery of cytokines is appealing compared to systemic deliveryfor a variety of reasons. It takes advantage of the natural biology ofcytokines that have evolved to act locally in a paracrine or autocrinefashion. Local expression also dramatically minimizes many of the sideeffects of systemic delivery of cytokines. Thus, compounds and methodsto increase local expression of IL-2 would be better tolerated than highdose IL-2 treatment, which would expand therapeutic utility ofstrategies that increase IL-2.

Additional targets include several candidate genes involved in apoptosisand cell survival, including the zinc-finger transcription factorAiolos. Aiolos is a transcription factor whose expression is restrictedto lymphoid lineages. Aiolos binds to the Bcl-2 promoter, and alsointeracts with the Bcl-2 and Bcl-XL proteins to promote cell survival.Upregulation of Aiolos expression, for example, can reduce apoptosis ofHIV-1 infected cells.

Likewise, expression of Aiolos in lung and breast cancers predictssignificantly reduced patient survival. Aiolos decreases expression of alarge set of adhesion-related genes, disrupting cell-cell andcell-matrix interactions, facilitating metastasis. Aiolos may alsofunction as an epigenetic driver of lymphocyte mimicry in certainmetastatic epithelial cancers. Thus, downregulation of Aiolos may reduceor eliminate metastasis.

Similarly, the casein kinase 1 family of proteins plays a role in themitotic spindle formation, DNA repair, and RNA metabolism. Knippschildet al., Cell Signal., 17:675-89 (2005). There are six isoforms inhumans: α, γ1, γ2, γ3, δ, and ε. CK1α has been shown to have ananti-apoptotic function; its inhibition increased Fas-induced apoptosis,whereas the overexpression of CK1α delayed BID-mediated cell death.Desagher et al., Mol Cell., 8:601-11 (2001). In addition, CK1α inhibitsTRAIL induced apoptosis by modification of the TNF receptor or FADD atthe death-inducing signaling complex (DISC). Thus, downregulation ofCK1α leads to enhancement of TRAIL-induced cell death. CK1α alsopromotes cell survival by interacting with the retinoid X receptor(RXR). Downregulation of CK1α enhances the apoptotic effect of RXRagonists. Likewise, the ikaros family of proteins are tumor suppressorsthat play a role in leukemia.

One mechanism to disrupt protein drivers of a disease is to decrease thecellular concentration of these proteins. For example, proteolyticdegradation of cellular proteins is essential to normal cell function.Hijacking this process, by targeting specific disease-related proteins,presents a mechanism for the treatment of disease. The irreversiblenature of proteolysis makes it well-suited to serve as a regulatoryswitch for controlling unidirectional processes.

Ubiquitin-mediated proteolysis begins with ligation of one or moreubiquitin molecules to a particular protein substrate. Ubiquitinationoccurs through the activity of ubiquitin-activating enzymes (E1),ubiquitin-conjugating enzymes (E2), and ubiquitin-protein ligases (E3),acting sequentially to attach ubiquitin to lysine residues of substrateproteins. The E3 ligases confer specificity to ubiquitination reactionsby binding directly to particular substrates.

SUMMARY OF THE DISCLOSURE

Provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from the group consisting of

each X is independently CH₂ or C(═O);

Y is C(═O), C(═O)—(CR^(6a)R^(6b))_(n1), C(═S), orC(═S)—(CR^(6e)R^(6d))_(n2);

R² is H, deuterium, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 3 to 10 membered heterocyclyl, or optionallysubstituted 5 to 10 membered heteroaryl;

ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈ carbocyclyl,or 3 to 10 membered heterocyclyl, each optionally substituted with oneor more R^(A);

R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) are eachindependently H, deuterium, hydroxyl, halogen, cyano, nitro, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;

each R^(3g) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;

each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl;

each R⁵ is independently H, deuterium, C₁-C₆ alkyl,

each R^(6a), R^(6b), R^(6c), R^(6d), R¹⁴, and R¹⁵ is independently H,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(6a) andR^(6b) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R^(6c) and R^(6d) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B);

each R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c),R¹⁶, and R¹⁷ is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄aralkyl, or optionally substituted C₃-C₈ carbocyclyl; or R^(7a) andR^(8a) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7b) andR^(8b) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7c) andR^(8c) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; wherein each ofC₆-C₁₀ aryl, C₇-C₁₄ aralkyl, C₃-C₈ carbocyclyl, and 3 to 7 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R⁹ is independently optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to 10membered heteroaryl, optionally substituted C₇-C₁₄ aralkyl, optionallysubstituted 3 to 10 membered heterocyclyl, or optionally substitutedC₃-C₈ carbocyclyl;

each of R^(10a), R^(10b), R¹², and R¹³ is independently H, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(11a), R^(11b), R^(11c), and R^(11d) is independently optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(A) is independently halogen, cyano, nitro, hydroxyl, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆alkyl, halogen, or cyano; or two geminal R^(B) form oxo;

m is an integer of 0, 1, 2, 3, 4, or 5;

n1 and n2 are each independently an integer of 0, 1, 2, or 3;

each p is independently an integer of 0, 1, or 2; and

each t is independently an integer of 0, 1, 2, 3, 4, or 5.

Also provided herein is a compound of Formula (III):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is selected from the group consisting of

each X is independently CH₂ or C(═O);

R^(Z) is —NR^(7a)R^(8a) or ring A; and ring A is C₆-C₁₀ aryl, 5 to 10membered heteroaryl, C₃-C₈ carbocyclyl, or 3 to 10 memberedheterocyclyl, each optionally substituted with one or more R^(A);

R² is H, deuterium, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 3 to 10 membered heterocyclyl, or optionallysubstituted 5 to 10 membered heteroaryl;

R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) are eachindependently H, deuterium, hydroxyl, halogen, cyano, nitro, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;

each R^(3g) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;

each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl;

each R⁵ is independently H, deuterium, C₁-C₆ alkyl,

each R^(6a), R^(6b), R^(6c), R^(6d), R¹⁴, and R¹⁵ is independently H,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(6a) andR^(6b) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R^(6c) and R^(6d) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B);

each R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c),R¹⁶, and R¹⁷ is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄aralkyl, or optionally substituted C₃-C₈ carbocyclyl; or R^(7a) andR^(8a) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7b) andR^(8b) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7c) andR^(8c) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R¹⁶ and R¹⁷together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; wherein each ofC₆-C₁₀ aryl, C₇-C₁₄ aralkyl, C₃-C₈ carbocyclyl, and 3 to 7 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R⁹ is independently optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to 10membered heteroaryl, optionally substituted C₇-C₁₄ aralkyl, optionallysubstituted 3 to 10 membered heterocyclyl, or optionally substitutedC₃-C₈ carbocyclyl;

each of R^(10a), R^(10b), R¹², and R¹³ is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(11a), R^(11b), R^(11c), and R^(11d) is independently optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(A) is independently halogen, cyano, nitro, hydroxyl, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆alkyl, halogen, or cyano; or two geminal R^(B) form oxo;

m is an integer of 0, 1, 2, 3, 4, or 5;

n1 is an integer of 0, 1, 2, or 3;

each p is independently an integer of 0, 1, or 2; and

each t is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

Additionally provided herein is a compound of Formula (IIa), (IIb), or(IIc):

or a pharmaceutically acceptable salt thereof, wherein:

each n is independently an integer of 0, 1, or 2;

one of R¹ and R² is selected from the group consisting of H, deuterium,hydroxyl, halogen, cyano, nitro, optionally substituted C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a), —O(CH₂)_(t)—NR^(7a)R^(8a),—C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c), —OR⁹, —SR^(10a), —C(O)OR^(10b),—C(O)R^(11a), —NR^(7d)C(O)R^(11b), —S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d),(C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionallysubstituted C₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 3 to 10 membered heterocyclyl, and optionallysubstituted 5 to 10 membered heteroaryl; and the other of R¹ and R² is

each R³ is independently H, deuterium, C₁-C₆ alkyl,

each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl;

L is

Z¹ is C(═O), C(═NH), S(O)₂, or (CH₂)_(k);

Z² is a bond, S, O, or NH;

Z³ is C(═O) or S(O)₂;

ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈ carbocyclyl,or 3 to 10 membered heterocyclyl, each optionally substituted with oneor more R^(A);

each of R^(a1), R^(a2), and R^(a1) is independently H, optionallysubstituted C₁-C₆alkyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted C₇-C₁₄ aralkyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(b1), R^(b2), and R^(c2) is independently H, hydroxyl,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(b1) andR^(c1) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R^(b2) and R^(c2) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B);

each R^(5a), R^(5b), R^(10a), and R^(10b) is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each of R^(6a) and R^(6b) is independently H, halogen, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl;

each R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c), R⁷,and R⁸ is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄aralkyl, or optionally substituted C₃-C₈ carbocyclyl; or R^(7a) andR^(8a) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7b) andR^(8b) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7c) andR^(8c) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R⁷ and R⁸together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; wherein each ofC₆-C₁₀ aryl, C₇-C₁₄ aralkyl, C₃-C₈ carbocyclyl, or 3 to 7 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R⁹ is independently optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to 10membered heteroaryl, optionally substituted C₇-C₁₄ aralkyl, optionallysubstituted 3 to 10 membered heterocyclyl, or optionally substitutedC₃-C₈ carbocyclyl;

each R^(11a), R^(11b), R^(11c), and R^(11d) is independently optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(A) is independently halogen, cyano, nitro, hydroxyl, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆alkyl, halogen, or cyano; or two geminal R^(B) form oxo;

m1, m2, m3, and m4 are each independently an integer of 0, 1, 2, 3, 4 or5;

k is an integer of 1, 2, 3, 4, 5 or 6; and

each t is independently an integer of 0, 1, 2, 3, 4, or 5.

In certain embodiments, in Formula (IIa), one of R¹ and R² is H, n is aninteger of 1 or 2, R³ is H, R⁴ is H, L is —CH₂—NH—C(═O)—NH—CH₂— or—CH₂—NH—C(═O)—NH—*, then ring A is not

wherein the symbol “*” indicates the attachment point to ring A.

In certain embodiments, in Formula (lib), R¹ is H, n is an integer of 1or 2, R³ is H, R⁴ is H, L is —NH—C(═O)—CH₂—*, —CH₂—NH—C(═O)—CH₂—*, or—CH₂—NH—C(═S)—NH—*, then ring A is not

wherein the symbol “*” indicates the attachment point to ring A.

In certain embodiments, in Formula (lib), R¹ is H, n is an integer of 1or 2, R³ is H, R⁴ is H, L is —NH—C(═O)—NH—, —CH₂—NH—C(═O)—NH—CH₂—, or—CH₂—NH—C(═O)—NH—*, then ring A is not

wherein the symbol “*” indicates the attachment point to ring A.

In certain embodiments, in Formula (IIc), R¹ is H, n is an integer of 1,R³ is H, R⁴ is H, L is —CH₂—NH—C(═O)—NH—*, then ring A is not

wherein the symbol “*” indicates the attachment point to ring A.

Furthermore, provided herein is a compound of Formula (IV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is selected from the group consisting of

each X is independently CH₂ or C(═O);

R^(Z) is —NR^(7a)R^(8a) or ring A; and ring A is C₆-C₁₀ aryl, 5 to 10membered heteroaryl, C₃-C₈ carbocyclyl, or 3 to 10 memberedheterocyclyl, each optionally substituted with one or more R^(A);

R² is H, deuterium, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 3 to 10 membered heterocyclyl, or optionallysubstituted 5 to 10 membered heteroaryl;

R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) are eachindependently H, deuterium, hydroxyl, halogen, cyano, nitro, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), s (O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;

each R^(3g) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;

each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl;

each R⁵ is independently H, deuterium, C₁-C₆ alkyl,

each R^(6a), R^(6b), R^(6c), R^(6d), R¹⁴, and R¹⁵ is independently H,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(6a) andR^(6b) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R^(6c) and R^(6d) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B);

each R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c),R¹⁶, and R¹⁷ is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄aralkyl, or optionally substituted C₃-C₈ carbocyclyl; or R^(7a) andR^(8a) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7b) andR^(8b) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7c) andR^(8c) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R¹⁶ and R¹⁷together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; wherein each ofC₆-C₁₀ aryl, C₇-C₁₄ aralkyl, C₃-C₈ carbocyclyl, and 3 to 7 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R⁹ is independently optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to 10membered heteroaryl, optionally substituted C₇-C₁₄ aralkyl, optionallysubstituted 3 to 10 membered heterocyclyl, or optionally substitutedC₃-C₈ carbocyclyl;

each of R^(11a), R^(10b), R¹², and R¹³ is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(11a), R^(11b), R^(11c), and R^(11d) is independently optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(A) is independently halogen, cyano, nitro, hydroxyl, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆alkyl, halogen, or cyano; or two geminal R^(B) form oxo;

m is an integer of 0, 1, 2, 3, 4, or 5;

n1 is an integer of 0, 1, 2, or 3;

each p is independently an integer of 0, 1, or 2; and

each t is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

Provided herein is a compound of Formula (V):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R¹ is selected from the group consisting of

each X is independently CH₂ or C(═O);

R^(Z) is —NR^(7a)R^(8a) or ring A; and ring A is C₆-C₁₀ aryl, 5 to 10membered heteroaryl, C₃-C₈ carbocyclyl, or 3 to 10 memberedheterocyclyl, each optionally substituted with one or more R^(A);

R² is H, deuterium, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 3 to 10 membered heterocyclyl, or optionallysubstituted 5 to 10 membered heteroaryl;

R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) are eachindependently H, deuterium, hydroxyl, halogen, cyano, nitro, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;

each R^(3g) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;

each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl;

each R⁵ is independently H, deuterium, C₁-C₆ alkyl,

each R^(6a), R^(6b), R^(6e), R^(6d), R¹⁴, and R¹⁵ is independently H,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(6a) andR^(6b) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R^(6c) and R^(6d) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B);

each R^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c),R¹⁶, and R¹⁷ is independently H, optionally substituted C₁-C₆ alkyl,optionally substituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄aralkyl, or optionally substituted C₃-C₈ carbocyclyl; or R^(7a) andR^(8a) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7b) andR^(8b) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R^(7c) andR^(8c) together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; or R¹⁶ and R¹⁷together with the nitrogen atom to which they are attached formoptionally substituted 3 to 7 membered heterocyclyl; wherein each ofC₆-C₁₀ aryl, C₇-C₁₄ aralkyl, C₃-C₈ carbocyclyl, and 3 to 7 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R⁹ is independently optionally substituted C₁-C₆ alkyl, optionallysubstituted C₂-C₆ alkenyl, optionally substituted C₂-C₆ alkynyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 5 to 10membered heteroaryl, optionally substituted C₇-C₁₄ aralkyl, optionallysubstituted 3 to 10 membered heterocyclyl, or optionally substitutedC₃-C₈ carbocyclyl;

each of R^(10a), R^(10b), R¹², and R¹³ is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(11a), R^(11b), R^(11c), and R^(11d) is independently optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl;

each R^(A) is independently halogen, cyano, nitro, hydroxyl, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B);

each R^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆alkyl, halogen, or cyano; or two geminal R^(B) form oxo;

m is an integer of 0, 1, 2, 3, 4, or 5;

n1 is an integer of 0, 1, 2, or 3;

each p is independently an integer of 0, 1, or 2; and

each t is independently an integer of 0, 1, 2, 3, 4, 5, 6, 7, or 8.

Provided herein is a pharmaceutical composition comprising a compoundprovided herein, e.g., a compound of Formula (I), (IIa), (IIb), (IIc),(III), (IV), or (V), or an enantiomer, a mixture of enantiomers, adiastereomer, a mixture of two or more diastereomers, a tautomer, amixture of two or more tautomers, or an isotopic variant thereof; or apharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof;and a pharmaceutically acceptable excipient.

Provided herein is a method of treating, ameliorating, or preventing adisease, disorder, or condition associated with a protein in a subject,comprising administering to the subject a therapeutically effectiveamount of a compound provided herein, e.g., a compound of Formula (I),(IIa), (IIb), (IIc), (III), (IV), or (V), or an enantiomer, a mixture ofenantiomers, a diastereomer, a mixture of two or more diastereomers, atautomer, a mixture of two or more tautomers, or an isotopic variantthereof; or a pharmaceutically acceptable salt, solvate, hydrate, orprodrug thereof.

In one embodiment, the protein is cytokine, aiolos, ikaros, helios,CK1α, or GSPT1. In another embodiment, the protein is IL-1β, IL-6, TNFα,or IL-2.

In one embodiment, the disease, disorder, or condition is inflammation,fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosingspondylitis, psoriasis, psoriatic arthritis, inflammatory boweldiseases, Crohn's disease, ulcerative colitis, uveitis, inflammatorylung diseases, chronic obstructive pulmonary disease, Alzheimer'sdisease, or cancer. In another embodiment, the disease, disorder, orcondition is cancer.

Provided herein is a method of modulating protein activity in a cell,comprising contacting the cell with a compound provided herein, e.g., acompound of Formula (I), (IIa), (IIb), (IIc), (III), (IV), or (V)), oran enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In one embodiment, the protein is a cytokine, aiolos, ikaros, helios,CK1α, or GSPT1. In another embodiment, the protein is IL-1β, IL-6, TNFα,or IL-2. In one embodiment, the method is to inhibit protein activity.In another embodiment, the method is to stimulate or activate proteinactivity.

DETAILED DESCRIPTION

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications referenced herein are incorporated by reference in theirentirety unless stated otherwise. In the event that there are aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise. As used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques, andpharmacology are employed. The use of “or” or “and” means “and/or”unless stated otherwise. Furthermore, use of the term “including” aswell as other forms, such as “include”, “includes,” and “included,” isnot limiting.

Unless otherwise defined, all terms (including technical and scientificterms) are to be given their ordinary and customary meaning to a personof ordinary skill in the art and are not to be limited to a special orcustomized meaning unless expressly so defined herein. It should benoted that the use of a particular terminology when describing certainfeatures or aspects of the disclosure should not be taken to imply thatthe terminology is being re-defined herein to be restricted to includeany specific characteristics of the features or aspects of thedisclosure with which that terminology is associated.

All numbers expressing quantities of ingredients, reaction conditions,and so forth used in the specification are to be understood as beingmodified in all instances by the term ‘about.’ Accordingly, unlessindicated to the contrary, the numerical parameters set forth herein areapproximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of anyclaims in any application claiming priority to the present application,each numerical parameter should be construed in light of the number ofsignificant digits and ordinary rounding approaches.

Furthermore, although the foregoing has been described in some detail byway of illustrations and examples for purposes of clarity andunderstanding, it is apparent to those skilled in the art that certainchanges and modifications may be practiced. Therefore, the descriptionand examples should not be construed as limiting the scope of theinvention to the specific embodiments and examples described herein, butrather to also cover all modification and alternatives coming with thetrue scope and spirit of the invention.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit,rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human subject. In one embodiment, the subject is ahuman.

The terms “treat,” “treating,” and “treatment” are meant to includealleviating or abrogating a disorder, disease, or condition, or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating the cause(s) of the disorder,disease, or condition itself.

The terms “prevent,” “preventing,” and “prevention” are meant to includea method of delaying and/or precluding the onset of a disorder, disease,or condition, and/or its attendant symptoms; barring a subject fromacquiring a disorder, disease, or condition; or reducing a subject'srisk of acquiring a disorder, disease, or condition.

The terms “alleviate” and “alleviating” refer to easing or reducing oneor more symptoms (e.g., pain) of a disorder, disease, or condition. Theterms can also refer to reducing adverse effects associated with anactive ingredient. Sometimes, the beneficial effects that a subjectderives from a prophylactic or therapeutic agent do not result in a cureof the disorder, disease, or condition.

The term “contacting” or “contact” is meant to refer to bringingtogether of a therapeutic agent and cell or tissue such that aphysiological and/or chemical effect takes place as a result of suchcontact. Contacting can take place in vitro, ex vivo, or in vivo. In oneembodiment, a therapeutic agent is contacted with a cell in cell culture(in vitro) to determine the effect of the therapeutic agent on the cell.In another embodiment, the contacting of a therapeutic agent with a cellor tissue includes the administration of a therapeutic agent to asubject having the cell or tissue to be contacted.

The terms “effective amount” and “therapeutically effective amount” areto be given their ordinary and customary meaning to a person of ordinaryskill in the art and refer without limitation to a sufficient amount ofan agent or a compound being administered which will relieve to someextent one or more of the symptoms of the disease or condition beingtreated. The result can be reduction and/or alleviation of the signs,symptoms, or causes of a disease, or any other desired alteration of abiological system. For example, an “effective amount” for therapeuticuses is the amount of the composition comprising a compound as disclosedherein required to provide a clinically significant decrease in adisease symptom. An appropriate “effective” amount in any individualcase may be determined using techniques, such as a dose escalationstudy. Where a drug has been approved by the U.S. Food and DrugAdministration (FDA) or a counterpart foreign medicines agency, a“therapeutically effective amount” optionally refers to the dosageapproved by the FDA or its counterpart foreign agency for treatment ofthe identified disease or condition.

As used herein, any “R” group(s) represent substituents that can beattached to the indicated atom. If two “R” groups are described as being“taken together,” the R groups and the atoms they are attached to canform a cycloalkyl, aryl, heteroaryl, or heterocycle. For example,without limitation, if R^(a) and R^(b), and the atom to which it isattached, are indicated to be “taken together” or “joined together,” itmeans that they are covalently bonded to one another to form a ring:

Whenever a group is described as being “optionally substituted,” thatgroup may be unsubstituted or substituted with one or more of theindicated substituents. Likewise, when a group is described as being“substituted,” the substituent may be selected from one or more of theindicated substituents. If no substituents are indicated, it is meantthat the indicated “optionally substituted” or “substituted” group maybe one or more group(s) individually and independently selected fromalkyl (e.g., C₁-C₆ alkyl); alkenyl (e.g., C₂-C₆ alkenyl); alkynyl (e.g.,C₂-C₆ alkynyl); C₃-C₈ carbocyclyl (e.g., C₃-C₈ cycloalkyl, C₃-C₈cycloalkenyl, or C₃-C₈ cyclalkynyl, each further optionally substituted,for example, with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆alkyl); (C₃-C₇ carbocyclyl)C₁-C₆ alkyl (further optionally substituted,for example, with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆alkyl); 5-10 membered heterocyclyl (further optionally substituted, forexample, with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆ alkyl);(5-10 membered heterocyclyl)C₁-C₆ alkyl (further optionally substituted,for example, with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆alkyl); aryl (further optionally substituted, for example, with halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆alkoxy)C₁-C₆ alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆ alkyl); (aryl)C₁-C₆ alkyl(further optionally substituted, for example, with halo, C₁-C₆ alkyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆alkyl, or —O(C₁-C₆ alkoxy)C₁-C₆ alkyl); 5-10 membered heteroaryl(further optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or—O(C₁-C₆ alkoxy)C₁-C₆ alkyl); (5-10 membered heteroaryl)C₁-C₆ alkyl(further optionally substituted with halo, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, or—O(C₁-C₆ alkoxy)C₁-C₆ alkyl); halo (e.g., fluoro, chloro, bromo, oriodo); cyano; hydroxy; protected hydroxy; alkoxy (e.g., C₁-C₆ alkoxy);haloalkyl (e.g., C₁-C₆ haloalkyl, such as —CF₃); haloalkyl (e.g., C₁-C₆haloalkoxy, such as —OCF₃); (C₁-C₆ alkoxy)C₁-C₆ alkyl; —O(C₁-C₆alkoxy)C₁-C₆ alkyl; (C₁-C₆ haloalkoxy)C₁-C₆ alkyl; —O(C₁-C₆haloalkoxy)C₁-C₆ alkyl; aryloxy; sulfhydryl (mercapto); alkylthio (e.g.,C₁-C₆ alkylthio); arylthio; azido; nitro; O-carbamyl; N-carbamyl;O-thiocarbamyl; N-thiocarbamyl; C-amido; N-amido; S-sulfonamido;N-sulfonamido; C-carboxy; protected C-carboxy; O-carboxy; acyl; cyanate;isocyanato; thiocyanato; isothiocyanato; silyl; sulfenyl; sulfinyl;sulfonyl; trihalomethanesulfonyl; trihalomethanesulfonamido; amino(including protected derivatives thereof); mono-substituted amino (forexample, NH(C₁-C₆ alkyl); di-substituted amino (for example, N(C₁-C₆alkyl)₂); oxo (═O); and thioxo (═S).

As used herein, “C_(a) to C_(b)” in which “a” and “b” are integers referto the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, orthe number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, or heterocyclyl group. That is, thealkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of thecycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of theheteroaryl, or ring of the heterocyclyl can contain from “a” to “b,”inclusive, carbon atoms. Thus, for example, a “C₁ to C₄ alkyl” grouprefers to all alkyl groups having from 1 to 4 carbons, that is, —CH₃,—CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, and—C(CH₃)₃. If no “a” and “b” are designated with regard to an alkyl,alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl,heteroaryl or heterocyclyl group, the broadest range described in thesedefinitions is to be assumed. As used herein, the term “C₁-C₆” includesC₁, C₂, C₃, C₄, C₅, and C₆, and a range defined by any of the twonumbers. For example, C₁-C₆ alkyl includes C₁, C₂, C₃, C₄, C₅, and C₆alkyl, C₂-C₆ alkyl, C₁-C₃ alkyl, etc. Similarly, C₃-C₈ carbocyclyl orcycloalkyl each include a hydrocarbon ring containing 3, 4, 5, 6, 7, or8 carbon atoms, or a range defined by any of the two numbers, such asC₃-C₇ cycloalkyl or C₅-C₆ cycloalkyl.

As used herein, “alkyl” refers to a straight or branched hydrocarbonchain that comprises a fully saturated (no double or triple bonds)hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms(whenever it appears herein, a numerical range such as “1 to 20” refersto each integer in the given range; e.g., “1 to 20 carbon atoms” meansthat the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 20 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated). The alkyl group may also be a mediumsize alkyl having 1 to 10 carbon atoms. The alkyl group could also be alower alkyl having 1 to 6 carbon atoms. The alkyl group of the compoundsmay be designated as “C₁-C₄ alkyl.” By way of example only, “C₁-C₄alkyl” indicates that there are one to four carbon atoms in the alkylchain, i.e., the alkyl chain is selected from methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkylgroups include, but are in no way limited to, methyl, ethyl, n-propyl,isopropyl, butyl, isobutyl, tertiary butyl, pentyl (straight chain orbranched), and hexyl (straight chain or branched). The alkyl group maybe substituted or unsubstituted.

The term “alkenyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon double bond(s) including, but not limited to, 1-propenyl,2-propenyl, 2-methyl-1-propenyl, 1-butenyl, and 2-butenyl. An alkenylgroup may be unsubstituted or substituted.

The term “alkynyl” used herein refers to a monovalent straight orbranched chain radical of from two to twenty carbon atoms containing acarbon triple bond(s) including, but not limited to, 1-propynyl,1-butynyl, and 2-butynyl. An alkynyl group may be unsubstituted orsubstituted.

As used herein, “cycloalkyl” refers to a completely saturated (no doubleor triple bonds) mono- or multi-cyclic hydrocarbon ring system. Whencomposed of two or more rings, the rings may be joined together in afused, bridged, or spiro fashion. As used herein, the term “fused”refers to two rings which have two atoms and one bond in common. As usedherein, the term “bridged cycloalkyl” refers to a cycloalkyl thatcontains a linkage of one or more atoms connecting non-adjacent atoms.As used herein, the term “spiro” refers to two rings which have one atomin common and the two rings are not linked by a bridge. Cycloalkylgroups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in thering(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s), or 3to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted orsubstituted. Examples of mono-cycloalkyl groups include, but are in noway limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Examples of fused cycloalkyl groups aredecahydronaphthalenyl, dodecahydro-1H-phenalenyl, andtetradecahydroanthracenyl. Examples of bridged cycloalkyl groups arebicyclo[1.1.1]pentyl, adamantanyl and norbornenyl. Examples of spirocycloalkyl groups include spiro[3.3]heptyl and spiro[4.5]decanyl.

As used herein, “carbocyclyl” refers to a mono- or multi-cyclichydrocarbon ring system. When composed of two or more rings, the ringsmay be joined together in a fused, bridged or spiro fashion, asdescribed herein. Carbocyclyl groups can contain 3 to 30 atoms in thering(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3to 8 atoms in the ring(s), or 3 to 6 atoms in the ring(s). A carbocyclylgroup may be unsubstituted or substituted. Multicyclic carbocyclylgroups can include, for example, a non-aromatic hydrocarbon ring fusedto an aromatic hydrocarbon ring. Examples of carbocyclyl groups include,but are in no way limited to, cycloalkyl groups and cycloalkenyl groups,as defined herein, as well as 1,2,3,4-tetrahydronaphthalyl,2,3-dihydro-1H-indenyl, 5,6,7,8-tetrahydroquinolinyl, and6,7-dihydro-5H-cyclopenta[b]pyridyl.

As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclicor multicyclic aromatic ring system (including fused ring systems wheretwo carbocyclic rings share a chemical bond) that has a fullydelocalized pi-electron system throughout all the rings. The number ofcarbon atoms in an aryl group can vary. For example, the aryl group canbe a C₆-C₁₄ aryl group, a C₆-C₁₀ aryl group or a C₆ aryl group. Examplesof aryl groups include, but are not limited to, phenyl, naphthyl, andazulenyl. An aryl group may be substituted or unsubstituted.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system (a ring system with fully delocalized pi-electronsystem) that contain(s) one or more heteroatoms (for example, 1, 2 or 3heteroatoms), that is, an element other than carbon, including but notlimited to, nitrogen, oxygen and sulfur. The number of atoms in thering(s) of a heteroaryl group can vary. For example, the heteroarylgroup can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in thering(s) or 5 to 6 atoms in the ring(s), such as nine carbon atoms andone heteroatom; eight carbon atoms and two heteroatoms; seven carbonatoms and three heteroatoms; eight carbon atoms and one heteroatom;seven carbon atoms and two heteroatoms; six carbon atoms and threeheteroatoms; five carbon atoms and four heteroatoms; five carbon atomsand one heteroatom; four carbon atoms and two heteroatoms; three carbonatoms and three heteroatoms; four carbon atoms and one heteroatom; threecarbon atoms and two heteroatoms; or two carbon atoms and threeheteroatoms. Furthermore, the term “heteroaryl” includes fused ringsystems where two rings, such as at least one aryl ring and at least oneheteroaryl ring or at least two heteroaryl rings, share at least onechemical bond. Examples of heteroaryl rings include, but are not limitedto, furanyl, furazanyl, thienyl, benzothienyl, phthalazinyl, pyrrolyl,oxazolyl, benzoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, thiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, benzothiazolyl, imidazolyl,benzimidazolyl, indolyl, indazolyl, pyrazolyl, benzopyrazolyl,isoxazolyl, benzoisoxazolyl, isothiazolyl, triazolyl, benzotriazolyl,thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, purinyl, pteridinyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, cinnolinyl, and triazinyl. A heteroaryl group may besubstituted or unsubstituted.

As used herein, “heterocyclyl” refers to three-, four-, five-, six-,seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic andtricyclic ring system, wherein carbon atoms together with from 1 to 5heteroatoms constitute said ring system. A heterocycle may optionallycontain one or more unsaturated bonds situated in such a way, however,that a fully delocalized pi-electron system does not occur throughoutall the rings (i.e., the ring system is not aromatic). The heteroatom(s)is an element other than carbon including, but not limited to, oxygen,sulfur, and nitrogen. A heterocycle may further contain one or morecarbonyl or thiocarbonyl functionalities, so as to make the definitioninclude oxo-systems and thio-systems such as lactams, lactones, cyclicimides, cyclic thioimides, and cyclic carbamates. When composed of twoor more rings, the rings may be joined together in a fused, bridged, orspiro fashion. As used herein, the term “fused” refers to two ringswhich have two atoms and one bond in common. As used herein, the term“bridged heterocyclyl” refers to a heterocyclyl containing a linkage ofone or more atoms connecting non-adjacent atoms. As used herein, theterm “spiro” refers to two rings which have one atom in common and thetwo rings are not linked by a bridge. Heterocyclyl groups can contain 3to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atomsin the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in thering(s). For example, five carbon atoms and one heteroatom; four carbonatoms and two heteroatoms; three carbon atoms and three heteroatoms;four carbon atoms and one heteroatom; three carbon atoms and twoheteroatoms; two carbon atoms and three heteroatoms; one carbon atom andfour heteroatoms; three carbon atoms and one heteroatom; or two carbonatoms and one heteroatom. Additionally, any nitrogens in a heterocyclylgroup may be quaternized. Heterocyclyl groups can be linked to the restof the molecule via a carbon atom in the heterocyclyl group (C-linked)or by a heteroatom in the heterocyclyl group, such as a nitrogen atom(N-linked). Heterocyclyl groups may be unsubstituted or substituted.Examples of such “heterocyclyl” groups include, but are not limited to,aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, 1,3-dioxinyl,1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl,1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,3-oxathiolanyl,1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl,tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimidyl, succinimidyle,barbituryl, thiobarbituryl, dioxopiperazinyl, hydantoinyl,dihydrouracyl, trioxanyl, hexahydro-1,3,5-triazinyl, imidazolinyl,imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl,oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl,N-oxopiperidinyl, piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl,2-oxopyrrolidinyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopyranyl,thiamorpholinyl, dioxothiomorpholinyl, oxothiomorpholinyl,benzimidazolidinonyl, tetrahydroquinolinyl, and3,4-methylenedioxyphenyl. Examples of spiro heterocyclyl groups include,but are not limited to, 2-azaspiro[3.3]heptanyl,2-oxaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl,2,6-diazaspiro[3.3]heptanyl, 2-oxaspiro[3.4]octanyl, and2-azaspiro[3.4]octanyl.

“Lower alkylene groups” are straight-chained —CH₂— tethering groups,forming bonds to connect molecular fragments via their terminal carbonatoms. Lower alkylene groups contain from 1 to 6 carbon atoms. Examplesinclude, but are not limited to, methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), and butylene (—CH₂CH₂CH₂CH₂—). A lower alkylenegroup can be substituted by replacing one or more hydrogen of the loweralkylene group with a substituent(s) listed under the definition of“substituted.”

As used herein, “aralkyl” and “(aryl)alkyl” refer to an aryl group, asdefined above, connected, as a substituent, via a lower alkylene group,as described above. The lower alkylene and aryl group of an aralkyl maybe substituted or unsubstituted. Examples include, but are not limitedto, benzyl, 2-phenylalkyl, 3-phenylalkyl, and naphthylalkyl.

As used herein, “heteroaralkyl” and “(heteroaryl)alkyl” refer to aheteroaryl group, as defined above, connected, as a substituent, via alower alkylene group, as defined above. The lower alkylene andheteroaryl group of heteroaralkyl may be substituted or unsubstituted.Examples include, but are not limited to, 2-thienylalkyl,3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl,isoxazolylalkyl, and imidazolylalkyl, and their benzo-fused analogs.

A “(heterocyclyl)alkyl” is a heterocyclic or a heterocyclyl group, asdefined above, connected, as a substituent, via a lower alkylene group,as defined above. The lower alkylene and heterocyclyl groups of a(heterocyclyl)alkyl may be substituted or unsubstituted. Examplesinclude, but are not limited to, (tetrahydro-2H-pyran-4-yl)methyl,(piperidin-4-yl)ethyl, (piperidin-4-yl)propyl,(tetrahydro-2H-thiopyran-4-yl)methyl, and (1,3-thiazinan-4-yl)methyl.

As used herein, “alkoxy” refers to the formula —OR, wherein R is analkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl or acycloalkynyl, as defined above. A non-limiting list of alkoxys ismethoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy,iso-butoxy, sec-butoxy, and tert-butoxy. An alkoxy may be substituted orunsubstituted.

As used herein, “acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, oraryl, as defined above, connected, as substituents, via a carbonylgroup. Examples include, but are not limited to, formyl, acetyl,propanoyl, benzoyl, and acryl.

As used herein, “hydroxyalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a hydroxy group. Exemplaryhydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkyl, di-haloalkyl, and tri-haloalkyl). Such groups include,but are not limited to, chloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, 1-chloro-2-fluoromethyl, and 2-fluoroisobutyl.

As used herein, “haloalkoxy” refers to an alkoxy group in which one ormore of the hydrogen atoms are replaced by a halogen (e.g.,mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). Such groups include,but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy,trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. Ahaloalkoxy may be substituted or unsubstituted.

As used herein, “aryloxy” and “arylthio” refers to RO— and RS—,respectively, in which R is an aryl, as defined above, such as phenyl.Both an aryloxy and arylthio may be substituted or unsubstituted.

A “sulfenyl” group refers to an “—SR” group in which R can be hydrogen,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl,heteroaryl, heterocyclyl, aralkyl, or heterocyclyl(alkyl), as definedabove. A sulfenyl may be substituted or unsubstituted.

A “sulfinyl” group refers to an “—S(═O)—R” group in which R can be thesame as defined with respect to sulfenyl. A sulfinyl may be substitutedor unsubstituted.

A “sulfonyl” group refers to an “SO₂R” group in which R can be the sameas defined with respect to sulfenyl. A sulfonyl may be substituted orunsubstituted.

An “O-carboxy” group refers to a “RC(═O)O—” group in which R can behydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined herein. An O-carboxy may be substitutedor unsubstituted.

The terms “ester” and “C-carboxy” refer to a “—C(═O)OR” group in which Rcan be the same as defined with respect to O-carboxy. An ester andC-carboxy may be substituted or unsubstituted.

A “thiocarbonyl” group refers to a “—C(═S)R” group in which R can be thesame as defined with respect to O-carboxy. A thiocarbonyl may besubstituted or unsubstituted.

A “trihalomethanesulfonyl” group refers to an “X₃CSO₂—” group wherein Xis a halogen.

A “trihalomethanesulfonamido” group refers to an “X₃CS(O)₂N(R)—” groupwherein X is a halogen and R is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkenyl, C₃-C₇ cycloalkynyl,aryl, 5 to 10 membered heteroaryl, 5 to 10 membered heterocyclyl,aralkyl, or (5 to 10 membered heterocyclyl)alkyl.

An “alkoxyalkyl” or “(alkoxy)alkyl” group refers to an alkoxy groupconnected via an lower alkylene group, such as C₂_C₈ alkoxyalkyl, or(C₁-C₆ alkoxy)C₁-C₆ alkyl, for example, —(CH₂)₁₋₃—OCH₃.

An “—O-alkoxyalkyl” or “—O-(alkoxy)alkyl” group refers to an alkoxygroup connected via an —O-(lower alkylene) group, such as —O—(C₁-C₆alkoxy)C₁-C₆ alkyl, for example, —O(CH₂)₁₋₃—OCH₃.

The terms “amino” and “unsubstituted amino” as used herein refer to a—NH₂ group. The term “mono-substituted amino group” as used hereinrefers to an amino (—NH₂) group where one of the hydrogen atom isreplaced by a substituent. The term “di-substituted amino group” as usedherein refers to an amino (—NH₂) group where each of the two hydrogenatoms is replaced by a substituent. In one embodiment, the substituentmay be independently C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇cycloalkyl, C₃-C₇ cycloalkenyl, C₃-C₇ cycloalkynyl, aryl, 5 to 10membered heteroaryl, 5 to 10 membered heterocyclyl, aralkyl, or (5 to 10membered heterocyclyl)alkyl, as defined herein.

As used herein, the term “hydroxy” refers to a —OH group.

The term “cyano” refers to a —CN group.

The term “azido” as used herein refers to a —N₃ group.

The term “isocyanato” refers to an —NCO group.

The term “thiocyanato” refers to a —CNS group.

The term “isothiocyanato” refers to an —NCS group.

The term “mercapto” refers to an —SH group.

The term “S-sulfonamido” refers to an —SO₂N(R₂) group in which each R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. An S-sulfonamido may besubstituted or unsubstituted.

The term “N-sulfonamido” group refers to an RSO₂N(R)— group in whicheach R is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. An N-sulfonamido may besubstituted or unsubstituted.

The term “O-carbamyl” refers to an —OC(═O)N(R₂) group in which each R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. An O-carbamyl may be substitutedor unsubstituted.

The term “N-carbamyl” refers to an ROC(═O)N(R)— group in which each R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. An N-carbamyl may be substitutedor unsubstituted.

The term “O-thiocarbamyl” refers to an —OC(═S)—N(R₂) group in which eachR is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. An O-thiocarbamyl may besubstituted or unsubstituted.

The term “N-thiocarbamyl” refers to an ROC(═S)N(R)— group in which eachR is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. An N-thiocarbamyl may besubstituted or unsubstituted.

The term “C-amido” refers to a —C(═O)N(R₂) group in which each R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. A C-amido may be substituted orunsubstituted.

The term “N-amido” refers to an RC(═O)N(R)— group in which each R isindependently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. An N-amido may be substituted orunsubstituted.

The term “urea” refers to an —N(R₂)—C(═O)—N(R₂)— group in which each Ris independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. A urea group may be substitutedor unsubstituted.

The term “thiourea” refers to an —N(R₂)—C(═S)—N(R₂)— group in which eachR is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aralkyl, orheterocyclyl(alkyl), as defined above. A thiourea group may besubstituted or unsubstituted.

The term “halogen atom” or “halogen” as used herein means any one of theradio-stable atoms of column 7 of the Periodic Table of the Elements,such as, fluorine, chlorine, bromine, and iodine.

Where the numbers of substituents are not specified (e.g., haloalkyl),there may be one or more substituents present. For example, “haloalkyl”may include one or more of the same or different halogens. As anotherexample, “C₁-C₃ alkoxyphenyl” may include one or more of the same ordifferent alkoxy groups containing one, two, or three atoms.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (See, Biochem. 11:942-944(1972)).

The term “pharmaceutically acceptable salt” as used herein is to begiven its ordinary and customary meaning to a person of ordinary skillin the art and refers without limitation to a salt of a compound thatdoes not cause significant irritation to an organism to which it isadministered and does not abrogate the biological activity andproperties of the compound. In certain embodiments, the salt is an acidaddition salt of the compound. Pharmaceutical salts can be obtained byreacting a compound with inorganic acids such as hydrohalic acid (e.g.,hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, andphosphoric acid. Pharmaceutical salts can also be obtained by reacting acompound with an organic acid such as aliphatic or aromatic carboxylicor sulfonic acids, for example, formic acid, acetic acid (AcOH),propionic acid, glycolic acid, pyruvic acid, malonic acid, maleic acid,fumaric acid, trifluoroacetic acid (TFA), benzoic acid, cinnamic acid,mandelic acid, succinic acid, lactic acid, malic acid, tartaric acid,citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid,ethanesulfonic acid, p-toluensulfonic acid, salicylic acid, stearicacid, muconic acid, butyric acid, phenylacetic acid, phenylbutyric acid,valproic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,benzenesulfonic acid, 2-naphthalenesulfonic acid, or naphthalenesulfonicacid. Pharmaceutical salts can also be obtained by reacting a compoundwith a base to form a salt such as an ammonium salt, an alkali metalsalt, such as a lithium, sodium or a potassium salt, an alkaline earthmetal salt, such as a calcium, magnesium or aluminum salt, a salt oforganic bases such as dicyclohexylamine, N-methyl-D-glucamine,tris(hydroxymethyl)methylamine, (C₁-C₇ alkyl)amine, cyclohexylamine,dicyclohexylamine, triethanolamine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, tromethamine, and salts with aminoacids such as arginine and lysine; or a salt of an inorganic base, suchas aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, or sodium hydroxide.

The term “solvate” as used herein is to be given its ordinary andcustomary meaning to a person of ordinary skill in the art and referswithout limitation to mean that the solvent is complexed with a compoundin a reproducible molar ratio, including, but not limited to, 0.5:1,1:1, or 2:1. Thus, the term “pharmaceutically acceptable solvate” refersto a solvate wherein the solvent is one that does not cause significantirritation to an organism to which it is administered and does notabrogate the biological activity and properties of the compound.

It is understood that, in any compound described herein having one ormore chiral centers, if an absolute stereochemistry is not expresslyindicated, then each center may independently be of R-configuration orS-configuration or a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, enantiomerically enriched, or maybe stereoisomeric mixtures, and include all diastereomeric, andenantiomeric forms. In addition, it is understood that, in any compounddescribed herein having one or more double bond(s) generatinggeometrical isomers that can be defined as E or Z, each double bond mayindependently be E or Z, or a mixture thereof. Stereoisomers areobtained, if desired, by methods such as, stereoselective synthesisand/or the separation of stereoisomers by chiral chromatographiccolumns.

Likewise, it is understood that, in any compound described, alltautomeric forms are also intended to be included.

Wherever a substituent is depicted as a di-radical (i.e., has two pointsof attachment to the rest of the molecule), it is to be understood thatthe substituent can be attached in any directional configuration unlessotherwise indicated. Thus, for example, a substituent depicted as -AE-or

includes the substituent being oriented such that the A is attached atthe leftmost attachment point of the molecule as well as the case inwhich A is attached at the rightmost attachment point of the molecule.

It is to be understood that, where compounds disclosed herein haveunfilled valencies, the valencies are to be filled with hydrogens and/ordeuteriums.

It is understood that the compounds described herein can be labeledisotopically or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. Substitution with isotopes such as deuteriummay afford certain therapeutic advantages resulting from greatermetabolic stability, such as, for example, increased in vivo half-lifeor reduced dosage requirements. Each chemical element as represented ina compound structure may include any isotope of said element. Forexample, in a compound structure a hydrogen atom may be explicitlydisclosed or understood to be present in the compound. At any positionof the compound that a hydrogen atom may be present, the hydrogen atomcan be any isotope of hydrogen, including, but not limited to,hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium).Thus, reference herein to a compound encompasses all potential isotopicforms unless the context clearly dictates otherwise.

It is understood that the methods and formulations described hereininclude the use of crystalline forms, amorphous phases, and/orpharmaceutically acceptable salts, solvates, hydrates, and conformers ofcompounds of preferred embodiments, as well as metabolites and activemetabolites of these compounds having the same type of activity. Aconformer is a structure that is a conformational isomer. Conformationalisomerism is the phenomenon of molecules with the same structuralformula but different conformations (conformers) of atoms about arotating bond. In certain embodiments, the compounds described hereinexist in solvated forms with pharmaceutically acceptable solvents suchas water or ethanol. In certain embodiments, the compounds describedherein exist in unsolvated form. Solvates contain either stoichiometricor non-stoichiometric amounts of a solvent and may be formed during theprocess of crystallization with pharmaceutically acceptable solventssuch as water or ethanol. Hydrates are formed when the solvent is water,or alcoholates are formed when the solvent is alcohol. In addition, thecompounds provided herein can exist in unsolvated as well as solvatedforms. In general, the solvated forms are considered equivalent to theunsolvated forms for the purposes of the compounds and methods providedherein. Other forms in which the compounds of preferred embodiments canbe provided include amorphous forms, milled forms, and nano-particulateforms.

Likewise, it is understood that the compounds described herein, such ascompounds of preferred embodiments, include the compound in any of theforms described herein (e.g., pharmaceutically acceptable salts,crystalline forms, amorphous form, solvated forms, enantiomeric forms,and tautomeric forms).

Compounds of Formulae (I) and (III)

In one embodiment, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein ringA, R¹, R², Y, and m are each as described herein.

In certain embodiments, X is CH₂. In certain embodiments, X is C(═O).

In one embodiment, the compound of Formula (I) has the structure of:

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih), pis an integer of 1. In certain embodiments, in any one of Formulae (I)and (Ia) to (Ih), p is an integer of 2. In certain embodiments, in anyone of Formulae (I) and (Ia) to (Ih), p is an integer of 0. In certainembodiments, in any one of Formulae (I) and (Ia) to (Ih), p is aninteger of 1 or 2.

In certain embodiments, in any one of Formulae (I) and (Ia) to (If),each of R^(1a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(if) is hydrogen.In certain embodiments, in Formula (I), (Ig), or (Ih), the correspondingR¹

is unsubstituted (i.e., —(R^(3g))₀) or substituted with one R^(3g)(i.e., —(R^(3g))₁). In certain embodiments, in Formula (I), (Ig), or(Ih), R^(3g) is halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl, for example,fluoro, methyl, or trifluoromethyl. In certain embodiments, in Formula(I), (Ig), or (Ih), the corresponding R¹ is substituted with two R^(3g)(i.e., —(R^(3g))₂). In certain embodiments, in Formula (I), (Ig), or(Ih), R^(3g) is halo, C₁-C₆ alkyl, or C₁-C₆ haloalkyl. In certainembodiments, in Formula (I), (Ig), or (Ih), R^(3g) is fluoro or methyl.In certain embodiments, in Formula (I), (Ig), or (Ih), R^(3g) is fluoro.In certain embodiments, in Formula (I), (Ig), or (Ih), R^(3g) is methyl.

In certain embodiments, R¹ is

In certain embodiments, R¹ is

optionally substituted with one R^(3g). In certain embodiments, R¹ iswherein R¹ is

optionally substituted with one R^(3g).

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih), R⁴is H. In certain embodiments, in any one of Formulae (I) and (Ia) to(Ih), R⁴ is methyl.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih), R⁵is H. In certain embodiments, in any one of Formulae (I) and (Ia) to(Ih), R⁵ is C₁-C₆ alkyl, for example, methyl, ethyl, or isopropyl. Incertain embodiments, in any one of Formulae (I) and (Ia) to (Ih), R⁵ is

wherein R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each independently H or C₁-C₆ alkyl.In one embodiment, in any one of Formulae (I) and (Ia) to (Ih), R⁵ is

(i.e., valyloxymethyl). In another embodiment, in any one of Formulae(I) and (Ia) to (Ih), R⁵ is

(i.e., L-valyloxymethyl). In yet another embodiment, in any one ofFormulae (I) and (Ia) to (Ih), R⁵ is

(i.e., D-valyloxymethyl). In certain embodiments, in any one of Formulae(I) and (Ia) to (Ih), R⁵ is

where R¹² and R¹³ are each independently H or C₁-C₆ alkyl. In oneembodiment, in any one of Formulae (I) and (Ia) to (Ih), R⁵ is

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih), R²is H. In certain embodiments, in any one of Formulae (I) and (Ia) to(Ih), R² is C₁-C₆ alkyl, for example, methyl, ethyl, or isopropyl. Incertain embodiments, in any one of Formulae (I) and (Ia) to (Ih), R² ismethyl. In certain embodiments, in any one of Formulae (I) and (Ia) to(Ih), R² is H or methyl.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih), Yis C(═O). In certain embodiments, in any one of Formulae (I) and (Ia) to(Ih), Y is C(═O)—(CR^(6a)R^(6b))_(n1), wherein each R^(6a), R^(6b), andn1 is as defined herein. In certain embodiments, in any one of Formulae(I) and (Ia) to (Ih), Y is C(═O)—(CH₂) or C(═O)—(CH₂)₂. In certainembodiments, in any one of Formulae (I) and (Ia) to (Ih), Y is C(═O),C(═O)—(CH₂), or C(═O)—(CH₂)₂.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, unsubstituted or substituted with one or more R^(A).In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is 5, 6, 9, or 10 membered heteroaryl containing 1, 2, or 3heteroatoms selected from the group consisting of N, O, and S, forexample, ring A is pyridyl, thienyl, furyl, pyrimidinyl, pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, orthiadiazolyl, each independently unsubstituted or substituted with oneor more R^(A). In one embodiment, in any one of Formulae (I) and (Ia) to(Ih), ring A is thienyl, unsubstituted or substituted with one or moreR^(A). In certain embodiments, in any one of Formulae (I) and (Ia) to(Ih), ring A is C₃-C₇ carbocyclyl, for example, cyclopentyl orcyclohexyl, each independently unsubstituted or substituted with one ormore R^(A). In certain embodiments, in any one of Formulae (I) and (Ia)to (Ih), ring A is 5, 6, 9, or 10 membered heterocyclyl containing 1, 2,or 3 heteroatoms selected from the group consisting of N, O, and S, forexample, ring A is

each optionally substituted with one or more R^(A). In certainembodiments, in any one of Formulae (I) and (Ia) to (Ih), ring A issubstituted with one, two, or three R^(A). In certain embodiments, inany one of Formulae (I) and (Ia) to (Ih), ring A is unsubstituted.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈ carbocyclyl,or 3 to 10 membered heterocyclyl, each of which is optionallysubstituted with one, two, or three substituents R^(A); wherein eachsubstituent R^(A) is independently (i) halogen, cyano, hydroxyl, C₁-C₆alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or—NR^(7d)C(O)R^(11b), or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10membered heterocyclyl, each of which is optionally substituted with oneor more R^(B).

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is C₆-C₁₀ aryl, optionally substituted with one, two, or threesubstituents R^(A); wherein each substituent R^(A) is independently (i)halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,—(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b), or (ii) phenyl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, each of which isoptionally substituted with one or more R^(B).

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, orcyclohexyl, each of which is optionally substituted with one, two, orthree substituents R^(A); wherein each substituent R^(A) isindependently (i) halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b), or(ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered heterocyclyl, eachof which is optionally substituted with one or more R^(B).

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, optionally substituted with one, two, or threesubstituents R^(A); wherein each substituent R^(A) is independently (i)halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,—(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b), or (ii) phenyl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, each of which isoptionally substituted with one or more R^(B).

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, orcyclohexyl, each of which is optionally substituted with one, two, orthree substituents R^(A), wherein each substituent R^(A) isindependently cyano, fluoro, chloro, bromo, methyl,trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,morpholinylmethyl, propyl, butyl, hydroxyl-butyl, cyclopropyl,methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl,methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or acetamido.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, optionally substituted with one, two, or threesubstituents R^(A), wherein each substituent R^(A) is independentlycyano, fluoro, chloro, bromo, methyl, trifluoromethyl-ethyl,trifluoromethyl, dimethylaminomethyl, morpholinylmethyl, propyl, butyl,hydroxyl-butyl, cyclopropyl, methylcyclopropyl,trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl, hydroxyl,methoxy, dimethylamino, or acetamido.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, orcyclohexyl, each of which is optionally substituted with one, two, orthree substituents R^(A), wherein each substituent R^(A) isindependently cyano, fluoro, chloro, bromo, methyl,trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,morpholinylmethyl, isopropyl, sec-butyl, tert-butyl,(hydroxyl-tert-butyl), cyclopropyl, methylcyclopropyl,trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl, hydroxyl,methoxy, dimethylamino, or acetamido.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, optionally substituted with one, two, or threesubstituents R^(A), wherein each substituent R^(A) is independentlycyano, fluoro, chloro, bromo, methyl, trifluoromethyl-ethyl,trifluoromethyl, dimethylaminomethyl, morpholinylmethyl, isopropyl,sec-butyl, tert-butyl, (hydroxyl-tert-butyl), cyclopropyl,methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl,methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or acetamido.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, cyanophenyl, fluorophenyl, chlorophenyl, bromophenyl,methylphenyl, (1-trifluoromethylethyl)-phenyl, trifluoromethylphenyl,dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl, isopropylphenyl,sec-butylphenyl, tert-butylphenyl, (hydroxyl-tert-butyl)phenyl,cyclopropylphenyl, (1-methylcyclopropyl)phenyl,(1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,(1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,dimethylaminophenyl, acetamidophenyl, difluorophenyl, dichlorophenyl,chloro-methylphenyl, methyl-tert-butylphenyl, dimethylphenyl,trimethylphenyl, trimethoxyphenyl, dimethyl-tert-butylphenyl,dimethylamino-methylphenyl, naphthyl, thienyl, isopropylthienyl,pyridyl, tert-butylcyclohexyl, piperidinyl, or tert-butylpiperidinyl.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl,4-methylphenyl, 4-(1-trifluoromethylethyl)phenyl,4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl, 4-sec-butylphenyl,3-tert-butylphenyl, 4-tert-butylphenyl, 4-(hydroxyl-tert-butyl)phenyl,4-cyclopropylphenyl, 4-(1-methylcyclopropyl)phenyl,4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-dimethylaminophenyl, 4-acetamidophenyl,3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl,3-methyl-4-tert-butylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl,2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl, piperdin-4-yl,or 4-tert-butylpiperidin-1-yl.

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),each R^(A) is independently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —SR^(10a), —C(O)OR^(10b),—NR^(7d)C(O)R^(11b), phenyl, or C₃-C₇ cycloalkyl, wherein each phenyland C₃-C₇ cycloalkyl is optionally substituted with one or more R^(B).In certain embodiments, in any one of Formulae (I) and (la) to (Ih),each R^(A) is independently —(CH₂)_(t)—NR^(7a)R^(8a) or—O(CH₂)_(t)—NR^(7a)R^(8a); where t is 0 or 1; and each R^(7a) and R^(8a)is independently C₁-C₆ alkyl, or R^(7a) and R^(8a) together with thenitrogen atoms to which they are attached form a 5 or 6 memberedheterocyclyl, for example,

In certain embodiments, in any one of Formulae (I) and (la) to (Ih),each R^(A) is independently —C(O)NR^(7b)R^(8b); where R^(7b) and R^(8b)are each independently C₁-C₆ alkyl, or R^(7b) and R^(8b) together withthe nitrogen atoms to which they are attached form a 5 or 6 memberedheterocyclyl, for example,

In certain embodiments, in any one of Formulae (I) and (la) to (Ih),each R^(A) is independently —C(O)OR^(10b), where R^(10b) is C₁-C₆ alkyl,for example, methyl. In certain embodiments, in any one of Formulae (I)and (la) to (Ih), each R^(A) is independently —NR^(7d)C(O)R^(11b), whereR^(7d) is H and R^(11b) is C₁-C₆ alkyl. In certain embodiments, in anyone of Formulae (I) and (Ia) to (Ih), each R^(A) is independentlyhalogen, methyl, isopropyl, t-butyl, isobutyl, hydroxyl, methoxy,ethoxy, propoxy, trifluoromethyl, trifluoromethoxy, —S(C₃H₇), —N(CH₃)₂,—N(C₂H₅)₂, —NHC(═O)CH₃, —CH₂N(CH₃)₂, —O(CH₂)₂N(CH₃)₂, —C(═O)NH₂,—C(═O)N(CH₃)₂, cyclopropyl, cyclopentyl, cyclohexyl,

phenyl,

In certain embodiments, in any one of Formulae (I) and (Ia) to (Ih),each R^(A) is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), —NR^(7d)C(O)R^(11b),phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered heterocyclyl, whereineach of phenyl, 5 to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to10 membered heterocyclyl is optionally substituted with one or moreR^(B).

In certain embodiments, each R^(A) is independently cyano, fluoro,chloro, bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,dimethylaminomethyl, morpholinylmethyl, propyl, butyl, hydroxyl-butyl,cyclopropyl, methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl,methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or acetamido

In certain embodiments, each R^(A) is independently cyano, fluoro,chloro, bromo, methyl, trifluoromethylethyl, trifluoromethyl,dimethylaminomethyl, morpholinyl, isopropyl, sec-butyl, tert-butyl,hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,trifluoromethylcyclopropyl, phenyl, methylpiperidinyl, hydroxyl,methoxy, dimethylamino, or acetamido.

In certain embodiments, each R^(A) is independently cyano, fluoro,chloro, bromo, methyl, 1-trifluoromethylethyl, trifluoromethyl,dimethylaminomethyl, morpholin-4-yl, isopropyl, sec-butyl, tert-butyl,hydroxyl-tert-butyl, cyclopropyl, 1-methylcyclopropyl,1-trifluoromethylcyclopropyl, phenyl, 1-methylpiperidin-4-yl, hydroxyl,methoxy, dimethylamino, or acetamido.

In certain embodiments, ring A is substituted with two substituents,such as C₁-C₆ alkyl and halogen; two C₁-C₆ alkyl (identical ordifferent); two halogens (identical or different); halogen and C₁-C₆alkoxy (e.g., methoxy, ethoxy, or isopropoxy); C₁-C₆ alkyl and C₁-C₆haloalkyl; C₁-C₆ alkyl and mono-substituted amino (e.g., —NH(C₁-C₆alkyl), such as —NHCH3 or —NHC2H₅); C₁-C₆ alkyl and di-substituted amino(e.g., —N(C₁-C₆ alkyl)₂, where the two C₁-C₆ alkyl may be identical ordifferent, such as —N(CH₃)₂, —N(CH₃)C₂H₅, or —N(C₂H₅)₂); halogen andmono-substituted amino (e.g., —NH(C₁-C₆ alkyl), such as —NHCH₃ or—NHC₂H₅); halogen and di-substituted amino (e.g., —N(C₁-C₆ alkyl)₂,where the two C₁-C₆ alkyl may be identical or different, such as—N(CH₃)₂, —N(CH₃)C₂H₅, or —N(C₂H₅)₂); C₁-C₆ haloalkyl andmono-substituted amino (e.g., —NH(C₁-C₆ alkyl), such as —NHCH₃ or—NHC₂H₅); C₁-C₆ haloalkyl and di-substituted amino (e.g., —N(C₁-C₆alkyl)₂, where the two C₁-C₆ alkyl may be identical or different, suchas —N(CH₃)₂, —N(CH₃)C₂H₅, or —N(C₂H₅)₂); C₁-C₆ alkyl and hydroxy; C₁-C₆alkyl and C₁-C₆ alkoxy (e.g., methoxy, ethoxy, or isopropoxy); C₁-C₆alkyl and —(CH₂)_(t)—NR^(7a)R^(8a) (where t is 0 or 1; each R^(7a) andR^(8a) is independently C₁-C₆ alkyl, or R^(7a) and R^(8a) together withthe nitrogen atoms to which they are attached form a 5 or 6 memberedheterocyclyl, such as

C₁-C₆ alkyl and —C(O)NR^(7b)R^(8b); C₁-C₆ alkoxy and —C(O)NR^(7b)R^(8b)(where, for —C(O)NR^(7b)R^(8b), each R^(7b) and R^(8b) is independentlyC₁-C₆ alkyl, or R^(7b) and R^(8b) together with the nitrogen atoms towhich they are attached form a 5 or 6 membered heterocyclyl, such as

C₁-C₆ alkyl and —NR^(7d)C(O)R^(11b) (where R^(7d) is H, and R^(11b) isC₁-C₆ alkyl).

In one embodiment, in any one of Formulae (I) and (Ia) to (Ih),

-   -   X, if present, is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

-   -    where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(3g), if present, is independently halogen or C₁-C₆        alkyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in any one of Formulae (I) and (Ia) to (Ih),

X, if present, is CH₂ or C(═O);

-   -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H or methyl;    -   R⁵ is H or valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(3g), if present, is independently fluoro or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (I) and (Ia) to (Ih),

-   -   X, if present, is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently cyano, fluoro, chloro, bromo, methyl,        trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,        morpholinylmethyl, propyl, butyl, hydroxyl-butyl, cyclopropyl,        methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl,        methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or        acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(3g), if present, is independently fluoro or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and n1 is an integer of 0, 1, 2, or        3.

In yet another embodiment, in any one of Formulae (I) and (Ia) to (Ih),

-   -   X, if present, is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently cyano, fluoro, chloro, bromo, methyl,        trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,        morpholinylmethyl, isopropyl, sec-butyl, tert-butyl,        hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(3g), if present, is independently fluoro or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (I) and (Ia) to (Ih),

-   -   X, if present, is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, cyanophenyl, fluorophenyl, chlorophenyl,        bromophenyl, methylphenyl, (1-trifluoromethylethyl)phenyl,        trifluoromethylphenyl, dimethylaminomethylphenyl,        morpholin-4-ylmethylphenyl, isopropylphenyl, sec-butylphenyl,        tert-butylphenyl, (hydroxyl-tert-butyl)phenyl,        cyclopropylphenyl, (1-methylcyclopropyl)-phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(3g), if present, is independently fluoro or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In still another embodiment, in any one of Formulae (I) and (Ia) to(Ih),

-   -   X, if present, is CH₂ or C(═O);    -   Y is C(═O), CH₂C(O), CH₂CH₂C(O);    -   ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl,        4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl,        4-methylphenyl, 4-(1-trifluoromethylethyl)-phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methyl-cyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(3g), if present, is independently fluoro or methyl;    -   m is an integer of 0, 1, or 2; and    -   p is an integer of 1 or 2.

In one embodiment, provided herein is a compound of Formula (Ia):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein ring A,R², R⁴, R⁵, R^(3a), Y, m, and p are each as defined herein.

In another embodiment, provided herein is a compound of Formula (Ib):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein ring A,R², R⁴, R⁵, R^(3b), X, Y, m, and p are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(Ic):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein ring A,R², R⁴, R⁵, R^(3c), X, Y, m, and p are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(Id):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein ring A,R², R⁴, R⁵, R^(3d), Y, m, and p are each as defined herein.

In yet another embodiment, provided herein is a compound of Formula(Ie):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein ring A,R², R⁴, R⁵, R^(3e), X, Y, m, and p are each as defined herein.

In still another embodiment, provided herein is a compound of Formula(If):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein ring A,R², R⁴, R⁵, R^(3f), X, Y, m, and p are each as defined herein.

In one embodiment, in any one of Formulae (Ia) to (If),

-   -   X, if present, is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

-   -    where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2;    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in any one of Formulae (Ia) to (If),

-   -   X, if present, is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H or methyl;    -   R⁵ is H or valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (Ia) to (If),

-   -   X, if present, is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently cyano, fluoro, chloro, bromo, methyl,        trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,        morpholinylmethyl, propyl, butyl, hydroxyl-butyl, cyclopropyl,        methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl,        methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or        acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (Ia) to (If),

X, if present, is CH₂ or C(═O);

-   -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently cyano, fluoro, chloro, bromo, methyl,        trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,        morpholinylmethyl, isopropyl, sec-butyl, tert-butyl,        hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (Ia) to (If),

-   -   X, if present, is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, cyanophenyl, fluorophenyl, chlorophenyl,        bromophenyl, methylphenyl, (1-trifluoromethylethyl)phenyl,        trifluoromethylphenyl, dimethylaminomethylphenyl,        morpholin-4-ylmethylphenyl, isopropylphenyl, sec-butylphenyl,        tert-butylphenyl, (hydroxyl-tert-butyl)phenyl,        cyclopropylphenyl, (1-methylcyclopropyl)phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In still another embodiment, in any one of Formulae (Ia) to (If),

-   -   X, if present, is CH₂ or C(═O);    -   Y is C(═O), CH₂C(O), CH₂CH₂C(O);    -   ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl,        4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl,        4-methylphenyl, 4-(1-trifluoromethylethyl)-phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methylcyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   m is an integer of 0, 1, or 2; and    -   p is an integer of 1 or 2.

In one embodiment, provided herein is a compound of Formula (Ig):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein ring A,R², R⁴, R⁵, R^(3g), X, Y, m, and p are each as defined herein.

In another embodiment, provided herein is a compound of Formula (Ih):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein ring A,R², R⁴, R⁵, R^(3g), X, Y, m, and p are each as defined herein.

In one embodiment, in Formula (Ig) or (Ih),

-   -   X is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

-   -    where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;    -   R^(3g) is halogen or C₁-C₆ alkyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in Formula (Ig) or (Ih),

-   -   X is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H or methyl;    -   R⁵ is H or valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in Formula (Ig) or (Ih),

-   -   X is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently cyano, fluoro, chloro, bromo, methyl,        trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,        morpholinylmethyl, propyl, butyl, hydroxyl-butyl, cyclopropyl,        methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl,        methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or        acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in Formula (Ig) or (Ih),

-   -   X is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently cyano, fluoro, chloro, bromo, methyl,        trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,        morpholinylmethyl, isopropyl, sec-butyl, tert-butyl,        hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2;    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in Formula (Ig) or (Ih),

-   -   X is CH₂ or C(═O);    -   Y is (C═O)—(CH₂)_(n1);    -   ring A is phenyl, cyanophenyl, fluorophenyl, chlorophenyl,        bromophenyl, methylphenyl, (1-trifluoromethylethyl)phenyl,        trifluoromethylphenyl, dimethylaminomethylphenyl,        morpholin-4-ylmethylphenyl, isopropylphenyl, sec-butylphenyl,        tert-butylphenyl, (hydroxyl-tert-butyl)phenyl,        cyclopropylphenyl, (1-methylcyclopropyl)phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in Formula (Ig) or (Ih),

-   -   X is CH₂ or C(═O);    -   Y is C(═O), CH₂C(O), CH₂CH₂C(O);    -   ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl,        4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl,        4-methylphenyl, 4-(1-trifluoromethylethyl)-phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methylcyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   p is an integer of 1 or 2; and m is an integer of 0, 1, or 2.

In still another embodiment, in Formula (Ig) or (Ih),

-   -   X is CH₂ or C(═O);    -   Y is C(═O) or CH₂C(O);    -   ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl,        3-chlorophenyl, 4-trifluoromethylphenyl, 3-tert-butylphenyl,        4-tert-butylphenyl, 4-(1-trifluoromethyl-cyclopropyl)phenyl,        3-methoxyphenyl, 4-methoxyphenyl, 3,4-difluorophenyl,        3,4-dichlorophenyl, 3-chloro-4-methylphenyl,        3-methyl-4-tert-butylphenyl, 3,5-dimethylphenyl,        2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl,        2,6-dimethyl-4-tert-butylphenyl, 2-naphthyl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl, or        4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is methyl;    -   m is an integer of 1 or 2; and    -   p is an integer of 1 or 2.

In one embodiment, provided herein is a compound of Formula (III):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R^(Z) is—NR^(7a)R^(8a) or ring A; and ring A, R¹, R², R^(6a), R^(6b), R^(7a),R^(8a), m, and n1 are each as defined herein for Formula (I).

In certain embodiments, R^(Z) is —NR^(7a)R^(8a), wherein R^(7a) andR^(8a) are each as defined herein for Formula (I). In certainembodiments, R^(Z) is —NR^(7a)R^(8a), wherein R^(7a) and R^(8a) are eachindependently H or optionally substituted C₁-C₆ alkyl. In certainembodiments, R^(Z) is —NHCH₃, —NHC₂H₅, —N(CH₃)₂, —N(CH₃)C₂H₅, or—N(C₂H₅)₂. In certain embodiments, R^(Z) is dimethylamino. In certainembodiments, R^(Z) is ring A as defined herein for Formula (I).

In one embodiment, provided herein is a compound of Formula (IIIa):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3a), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In another embodiment, provided herein is a compound of Formula (IIIb):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(6b), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(IIIc):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3c), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(IIId):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3d), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(IIIe):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3e), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In still another embodiment, provided herein is a compound of Formula(IIIf):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3f), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In one embodiment, in any one of Formulae (IIIa) to (IIIf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) amino, mono-substituted amino, or di-substituted        amino; or (b) C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

-   -    where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is independently H or C₁-C₆ alkyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in any one of Formulae (IIIa) to (IIIf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) mono-substituted amino or di-substituted amino;        or (b) phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is independently H or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3,

In yet another embodiment, in any one of Formulae (IIIa) to (IIIf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) dimethylamino; or (b) phenyl, naphthyl, thienyl,        pyridyl, piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, propyl, butyl,        hydroxyl-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (IIIa) to (IIIf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, naphthyl, thienyl, pyridyl,        piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, isopropyl, sec-butyl,        tert-butyl, hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (IIIa) to (IIIf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, cyanophenyl, fluorophenyl,        chlorophenyl, bromophenyl, methylphenyl,        (1-trifluoromethylethyl)phenyl, trifluoromethylphenyl,        dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl,        isopropylphenyl, sec-butylphenyl, tert-butylphenyl,        (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl,        (1-methylcyclopropyl)phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;

R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present, is H;

-   -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In still another embodiment, in any one of Formulae (IIIa) to (IIIf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,        4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethylethyl)phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methylcyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In one embodiment, provided herein is a compound of Formula (IIIg):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In another embodiment, provided herein is a compound of Formula (IIIh):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(IIIi):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In one embodiment, in any one of Formulae (IIIg) to (IIIi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) amino, mono-substituted amino, or di-substituted        amino; or (b) C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;

-   -   R^(3g) is halogen or C₁-C₆ alkyl;    -   each R^(6a) and R^(6b) is independently H or C₁-C₆ alkyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in any one of Formulae (IIIg) to (IIIi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) mono-substituted amino or di-substituted amino;        or (b) phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is independently H or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3,

In yet another embodiment, in any one of Formulae (IIIg) to (IIIi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) dimethylamino; or (b) phenyl, naphthyl, thienyl,        pyridyl, piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, propyl, butyl,        hydroxyl-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (IIIg) to (IIIi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, naphthyl, thienyl, pyridyl,        piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, isopropyl, sec-butyl,        tert-butyl, hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (IIIg) to (IIIi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, cyanophenyl, fluorophenyl,        chlorophenyl, bromophenyl, methylphenyl,        (1-trifluoromethylethyl)phenyl, trifluoromethylphenyl,        dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl,        isopropylphenyl, sec-butylphenyl, tert-butylphenyl,        (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl,        (1-methylcyclopropyl)phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In yet another embodiment, in any one of Formulae (IIIg) to (IIIi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,        4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethylethyl)phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methylcyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In still another embodiment, in any one of Formulae (IIIg) to (IIIi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl,        3-tert-butylphenyl, 4-tert-butylphenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 3-methoxyphenyl,        4-methoxyphenyl, 3,4-difluoropheny, 13,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        2-naphthyl, 5-isopropylthien-2-yl, 4-pyridyl,        4-tert-butylcyclohexyl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is methyl;    -   m is an integer of 1 or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In one embodiment, the compound of Formula (I) is:

-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-1;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-2;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-3;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide    I-4;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-5;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-6;-   2-(4-dimethylaminophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-7;-   2-phenyl-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-8;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(thiophen-2-yl)-2-oxoacetamide    I-9;-   (S)-2-(4-(tert-butyl)phenyl)-N-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-10;-   2-(4-methoxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-11;-   2-(4-cyclopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-12;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-13;-   2-(4-isopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-14;-   2-(4-(sec-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-15;-   2-(4-hydroxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-16;-   2-(4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-17;-   2-(4-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-18;-   2-(3-tert-butylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-19;-   2-(4-acetamidophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-20;-   2-([1,1′-biphenyl]-4-yl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-21;-   2-(4-fluorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-22;-   2-(4-trifluoromethylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-23;-   2-(3,4-dichlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-24;-   2-(4-((dimethylamino)methyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-25;-   2-(4-(morpholinomethyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-26;-   2-(3-methyl-4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-27;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-28;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-29; or-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-30;    or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is:

-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-1;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-3;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide    I-4;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-6;-   2-(4-dimethylaminophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-7;-   2-phenyl-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-8;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(thiophen-2-yl)-2-oxoacetamide    I-9;-   2-(4-methoxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-11;-   2-(4-cyclopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-12;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-13;-   2-(4-isopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-14;-   2-(4-(sec-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-15;-   2-(4-hydroxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-16;-   2-(4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-17;-   2-(4-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-18;-   2-(3-tert-butylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-19;-   2-(4-acetamidophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-20;-   2-([1,1′-biphenyl]-4-yl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-21;-   2-(4-fluorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-22;-   2-(4-trifluoromethylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-23;-   2-(3,4-dichlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-24;-   2-(4-((dimethylamino)methyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-25;-   2-(4-(morpholinomethyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-26;-   2-(3-methyl-4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-27;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)-2-oxoacetamide    I-31;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-2-(4-(1,1,1-trifluoropropan-2-yl)phenyl)acetamide    I-36;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-40;-   2-(4-(tert-butyl)phenyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)-2-oxoacetamide    I-41;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-methylcyclopropyl)phenyl)-2-oxoacetamide    I-42;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)-2-oxoacetamide    I-43;-   2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide    I-44; or-   N¹-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-N²,N²-dimethyloxalamide    I-70;    or an enantiomer, a mixture of enantiomers, a diastereomer, a    mixture of two or more diastereomers, a tautomer, a mixture of two    or more tautomers, or an isotopic variant thereof; or a    pharmaceutically acceptable salt, solvate, hydrate, or prodrug    thereof.

In yet another embodiment, provided herein is:

-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-2;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-5;-   (S)-2-(4-(tert-butyl)phenyl)-N-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-10;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-32;-   2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-33;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-N-methyl-2-oxoacetamide    I-34;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide    I-37;-   N-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-52;-   2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-53;-   2-(3-methyl-4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-55;-   N-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-60;-   2-(4-(tert-butyl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-62;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)propanamide    I-63;-   2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-68;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-phenylacetamide    I-83;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6-trimethoxyphenyl)acetamide    I-84;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6-trimethylphenyl)acetamide    I-85;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2-fluorophenyl)acetamide    I-86;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-trifluoromethylphenyl)acetamide    I-87;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-methoxyphenyl)-2-oxoacetamide    I-89;-   2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-90;-   2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-91;-   2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-93;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-methoxyphenyl)-2-oxoacetamide    I-95;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(naphthalen-2-yl)-2-oxoacetamide    I-97;-   2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-99;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-fluorophenyl)-2-oxoacetamide    I-100;-   2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-102;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(pyridin-4-yl)acetamide    I-103; or-   2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide    I-104;    or an enantiomer, a mixture of enantiomers, a diastereomer, a    mixture of two or more diastereomers, a tautomer, a mixture of two    or more tautomers, or an isotopic variant thereof; or a    pharmaceutically acceptable salt, solvate, hydrate, or prodrug    thereof.

In yet another embodiment, provided herein is:

-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-28;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-29;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-30;-   2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-46;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-N-methyl-2-oxoacetamide    I-47;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-48;-   (2R)-(3-(4-((2-(4-(tert-butyl)phenyl)-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl    2-amino-3-methylbutanoate I-49;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-50;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-51;-   2-(3-methyl-4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-54;-   2-(4-(tert-butyl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-oxoacetamide    I-56;-   N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-57;-   N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-58;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide    I-59;-   2-(4-(tert-butyl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-61;-   (2,6-dioxo-3-(1-oxo-4-((2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)-phenyl)acetamido)methyl)isoindolin-2-yl)piperidin-1-yl)methyl    D-valinate I-64;-   N-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    I-65;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(piperidin-4-yl)phenyl)acetamide    I-66;-   2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-67;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(p-tolyl)acetamide    I-72;-   2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-73;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-phenylacetamide    I-74;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(trifluoromethyl)phenyl)acetamide    I-75;-   2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-76;-   2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-77;-   2-(4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-78;-   2-(2,4,6-trimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-79;-   2-(2,4,6-trimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-80;-   2-(4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-81;-   2-(2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-82;-   2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-88;-   2-(3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-92;-   2-(3-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-94;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-(naphthalen-2-yl)-2-oxoacetamide    I-96;-   2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-98;-   2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-101;-   2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-105; or-   2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-106;    or an enantiomer, a mixture of enantiomers, a diastereomer, a    mixture of two or more diastereomers, a tautomer, a mixture of two    or more tautomers, or an isotopic variant thereof; or a    pharmaceutically acceptable salt, solvate, hydrate, or prodrug    thereof.

In still another embodiment, provided herein is:

-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide    I-35;-   2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)methyl)-2-oxoacetamide    I-38;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)-2-oxoacetamide    I-39;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide    I-45;-   N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxo-4-phenylbutanamide    I-69; or-   N¹-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-N²,N²-dimethyloxalamide    I-71;    or an enantiomer, a mixture of enantiomers, a diastereomer, a    mixture of two or more diastereomers, a tautomer, a mixture of two    or more tautomers, or an isotopic variant thereof; or a    pharmaceutically acceptable salt, solvate, hydrate, or prodrug    thereof.

Compounds of Formulae (IIa), (IIb), and (IIc)

In one embodiment, provided herein is a compound of Formula (IIa),(IIb), or (IIc):

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,and n are each as described herein.

In certain embodiments, in Formula (IIa), one of R¹ and R² is H, n is 1or 2, R³ is H, R⁴ is H, L is —CH₂—NH—C(═O)—NH—CH₂— or—CH₂—NH—C(═O)—NH—*, then ring A is not

wherein the symbol “*” indicates the attachment point to ring A. Incertain embodiments, in Formula (IIb), R¹ is H, n is 1 or 2, R³ is H, R⁴is H, L is —NH—C(═O)—CH₂—*, —CH₂—NH—C(═O)—CH₂—*, or —CH₂—NH—C(═S)—NH—*,then ring A is not

wherein the symbol “*” indicates the attachment point to ring A. Incertain embodiments, in Formula (IIb), R¹ is H, n is 1 or 2, R³ is H, R⁴is H, L is —NH—C(═O)—NH—, —CH₂—NH—C(═O)—NH—CH₂—, or —CH₂—NH—C(═O)—NH—*,then ring A is not

wherein the symbol “*” indicates the attachment point to ring A. Incertain embodiments, in Formula (IIc), R¹ is H, n is 1, R³ is H, R⁴ isH, L is —CH₂—NH—C(═O)—NH—*, then ring A is not

wherein the symbol “*” indicates the attachment point to ring A.

In certain embodiments, in Formula (IIa), (IIb), or (IIc), one of R¹ andR² is H. In certain embodiments, in Formula (IIa), (IIb) or (IIc), R¹ isH. In certain embodiments, in Formula (IIa), (IIb), or (IIc), R² is H.

In certain embodiments, in Formula (IIa), (IIb), or (IIc), n is 1. Incertain embodiments, in Formula (IIa), (IIb), or (IIc), n is 2. Incertain embodiments, in Formula (IIa), (IIb), or (IIc), n is 0.

In certain embodiments, in Formula (IIa), (IIb), or (IIc), R³ is H. Incertain embodiments, in Formula (IIa), (IIb), or (IIc), R³ is C₁-C₆alkyl, for example, methyl, ethyl, or isopropyl. In certain embodiments,in Formula (IIa), (IIb), or (IIc), R³ is

and wherein R^(5a) and R^(5b) are each independently H or C₁-C₆ alkyl.In certain embodiments, in Formula (IIa), (IIb), or (IIc), R³ is

In certain embodiments, in Formula (IIa), (IIb), or (IIc), R³ is

wherein R⁷ and R⁸ are each H, and R^(6a) and R^(6b) are eachindependently H or optionally substituted C₁-C₆ alkyl. In certainembodiments, in Formula (IIa), (IIb), or (IIc), R³ is

wherein

R⁷ and R⁸ are each H; and R^(6a) and R^(6b) are each as defined herein.In certain embodiments, in Formula (IIa), (IIb), or (IIc), R³ is

wherein R⁷ and R⁸ together with the nitrogen atom to which they areattached form optionally substituted 3 to 7 membered heterocyclyl; andR^(6a) and R^(6b) are each as defined herein. In certain embodiments, inFormula (IIa), (IIb), or (IIc), R³ is valyloxymethyl. In one embodiment,R³ is L-valyloxymethyl. In another embodiment, R³ is D-valyloxymethyl.

In certain embodiments, in Formula (IIa), (IIb) or (IIc), R⁴ is H. Incertain embodiments, in Formula (IIa), (IIb) or (IIc), R⁴ is C₁-C₆alkyl, for example, methyl, ethyl, or isopropyl.

In certain embodiments, in Formula (IIa), (IIb) or (IIc), L is

In certain embodiments, each R^(a1) and R^(a2) is independently H orC₁-C₆ alkyl, for example, methyl. In certain embodiments, Z² is a bond.In certain embodiments, Z² is O. In certain embodiments, one of R^(b1)and R^(c1) is H, halogen, C₁-C₆ alkyl, or C₁-C₆haloalkyl; and the otherone of R^(b1) and R^(c1) is halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)₂, or hydroxyl. Incertain embodiments, R^(b1) is H, and R^(c1) is hydroxyl,trifluoromethyl, methyl, ethyl, isopropyl, cyclopropyl, methoxy, —NH₂,—NHCH₃, —NHC₂H₅, —N(CH₃)₂, or —N(C₂H₅)₂, or R^(b1) is fluoro ortrifluoromethyl, and R^(c1) is fluoro or hydroxyl. In certainembodiments, R^(b1) and R^(c1) together with the carbon atom to whichthey are attached form a C₃-C₇ cycloalkyl optionally substituted withone or more R^(B), for example, a cyclopropyl optionally substitutedwith a halogen or trifluoromethyl. In certain embodiments, both R^(b1)and R^(c1) are H, and L is

In one embodiment, L is

In another embodiment, L is

In yet another embodiment, L is

In certain embodiments, each m1 is independently 0, 1, or 2. In certainembodiments, each m2 is independently 0, 1, 2, or 3. For example, thecombination of m1 and m2 may be 0 and 1; 1 and 0; 1 and 1; 2 and 1; 1and 2; or 1 and 3. In certain embodiments, k is 3, 4, or 5. In certainembodiments, L is connected to ring A on the right side.

In certain embodiments, in Formula (IIa), (IIb), or (IIc), L is

In certain embodiments, R^(a3) is H or C₁-C₆ alkyl (for example,methyl). In certain embodiments, L is

where the —(CH₂)— on the right side of L has m4 minus 1 repeating units.In certain embodiments, each m3 is independently 0, 1, or 2. In certainembodiments, each m4 is independently 1, 2, or 3. For example, thecombination of m3 and m4 may be 0 and 1; 1 and 1; 2 and 1; 1 and 2; or 1and 3. In certain embodiments, both R^(b2) and R^(c2) are H. In certainembodiments, one of R^(b2) and R^(c2) is H, halogen, C₁-C₆ alkyl, orC₁-C₆haloalkyl, and the other one of R^(b2) and R^(c2) is halogen, C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇ cycloalkyl, —NH₂, —NH(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)₂, or hydroxyl. In certain embodiments, R^(b2) is H andR^(c2) is hydroxyl, trifluoromethyl, methyl, ethyl, isopropyl,cyclopropyl, methoxy, —NH₂, —NHCH₃, —NHC₂H₅, —N(CH₃)₂, or —N(C₂H₅)₂, orR^(b2) is fluoro or trifluoromethyl, and R^(c2) is fluoro or hydroxyl.In certain embodiments, R^(b2) and R^(c2) together with the carbon atomto which they are attached form a C₃-C₇ cycloalkyl optionallysubstituted with one or more R^(B), for example, a cyclopropyloptionally substituted with a halogen or trifluoromethyl. In certainembodiments, L is connected to ring A on the right side.

In certain embodiments, in Formula (IIa), (IIb) or (IIc), ring A isphenyl, unsubstituted or substituted with one or more R^(A). In certainembodiments, ring A is 5, 6, 9, or 10 membered heteroaryl containing 1,2, or 3 heteroatoms selected from the group consisting of N, O, and S,for example, ring A is pyridyl, thienyl, furyl, pyrimidinyl, pyrazolyl,imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, orthiadiazolyl, each independently unsubstituted or substituted with oneor more R^(A). In one embodiment, ring A is thienyl, unsubstituted orsubstituted with one or more R^(A). Other non-limiting examples of ringA may be selected from the group consisting of

each of which is optionally substituted with one or more R^(A). Incertain embodiments, ring A is C₃-C₇ carbocyclyl, C₃-C₇ cycloalkyl, orC₅-C₇ cycloalkyl, for example, cyclopentyl or cyclohexyl, eachindependently unsubstituted or substituted with one or more R^(A). Incertain embodiments, ring A is 5, 6, 9, or 10 membered heterocyclylcontaining 1, 2, or 3 heteroatoms selected from the group consisting ofN, O, and S, for example, ring A is

each of which is optionally substituted with one or more R^(A). Incertain embodiments, ring A is substituted with one, two, or threeR^(A). In certain embodiments, ring A is unsubstituted.

In certain embodiments, in Formula (IIa), (IIb) or (IIc), each R^(A) isindependently halogen, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a), —O(CH₂)_(t)—NR^(7a)R^(8a),—C(O)NR^(7b)R^(8b), —C(O)OR^(10b), —NR^(7d)C(O)R^(11b), phenyl, or C₃-C₇cycloalkyl, wherein each phenyl and C₃-C₇ cycloalkyl is optionallysubstituted with one or more R^(B). In certain embodiments, R^(A) is—(CH₂)_(t)—NR^(7a)R^(8a) or —O(CH₂)_(t)—NR^(7a)R^(8a); t is 0 or 1; andeach R^(7a) and R^(8a) is independently C₁-C₆ alkyl, or R^(7a) andR^(8a) together with the nitrogen atoms to which they are attached forma 5 or 6 membered heterocyclyl, for example,

In certain embodiments, R^(A) is —C(O)NR^(7b)R^(8b); each R^(7b) andR^(8b) is independently C₁-C₆ alkyl, or R^(7b) and R^(8b) together withthe nitrogen atoms to which they are attached form a 5 or 6 memberedheterocyclyl, for example,

In certain embodiments, R^(A) is —C(O)OR^(10b), and R^(10b) is C₁-C₆alkyl, for example, methyl. In certain embodiments, R^(A) is—NR^(7d)C(O)R^(11b), R^(7d) is H, and R^(11b) is C₁-C₆ alkyl. In certainembodiments, R^(A) is —SR^(10a), and R^(10a) is C₁-C₆ alkyl. In certainembodiments, each R^(A) is independently halogen, methyl, isopropyl,t-butyl, isobutyl, hydroxyl, methoxy, ethoxy, propoxy, trifluoromethyl,trifluoromethoxy, —S(C₃H₇), —N(CH₃)₂, —N(C₂H₅)₂, —NHC(═O)CH₃,—CH₂N(CH₃)₂, —O(CH₂)₂N(CH₃)₂, —C(═O)NH₂, —C(═O)N(CH₃)₂, cyclopropyl,cyclopentyl, cyclohexyl,

phenyl,

In certain embodiments, ring A is substituted with two substituents,such as C₁-C₆ alkyl and halogen; two C₁-C₆alkyl (identical ordifferent); two halogens (identical or different); halogen and C₁-C₆alkoxy (e.g., methoxy, ethoxy, or isopropoxy); C₁-C₆ alkyl and C₁-C₆haloalkyl; C₁-C₆ alkyl and mono-substituted amino (e.g., —NH(C₁-C₆alkyl), such as —NHCH₃ or —NHC₂H₅); C₁-C₆ alkyl and di-substituted amino(e.g., —N(C₁-C₆ alkyl)₂, where the two C₁-C₆ alkyl may be identical ordifferent, such as —N(CH₃)₂, —N(CH₃)C₂H₅, or —N(C₂H₅)₂); halogen andmono-substituted amino (e.g., —NH(C₁-C₆ alkyl), such as —NHCH₃ or—NHC₂H₅); halogen and di-substituted amino (e.g., —N(C₁-C₆ alkyl)₂,where the two C₁-C₆alkyl may be identical or different, such as—N(CH₃)₂, —N(CH₃)C₂H₅, or —N(C₂H₅)₂); C₁-C₆ haloalkyl andmono-substituted amino (e.g., —NH(C₁-C₆ alkyl), such as —NHCH₃ or—NHC₂H₅); C₁-C₆haloalkyl and di-substituted amino (e.g., —N(C₁-C₆alkyl)₂, where the two C₁-C₆ alkyl may be identical or different, suchas —N(CH₃)₂, —N(CH₃)C₂H₅, or —N(C₂H₅)₂); C₁-C₆ alkyl and hydroxy;C₁-C₆alkyl and C₁-C₆ alkoxy (e.g., methoxy, ethoxy, or isopropoxy);C₁-C₆ alkyl and —(CH₂)_(t)—NR^(7a)R^(8a) (where t is 0 or 1; and eachR^(7a) and R^(8a) is independently C₁-C₆ alkyl, or R^(7a) and R^(8a)together with the nitrogen atoms to which they are attached form a 5 or6 membered heterocyclyl, such as

C₁-C₆ alkyl and —C(O)NR^(7b)R^(8b); C₁-C₆ alkoxy and —C(O)NR^(7b)R^(8b)(for —C(O)NR^(7b)R^(8b), each R^(7b) and R^(8b) is independently C₁-C₆alkyl, or R^(7b) and R^(8b) together with the nitrogen atoms to whichthey are attached form a 5 or 6 membered heterocyclyl, such as

C₁-C₆ alkyl and —NR^(7a-)C(O)R^(11b) (where R^(7d) is H and R^(11b) isC₁-C₆ alkyl).

In one embodiment, provided herein is:

-   1-(3-(dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-1;-   1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)urea    II-2;-   (S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-3;-   1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-methoxy-4-methylphenyl)urea    II-4;-   1-(4-chloro-3-(trifluoromethoxy)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-5;-   1-(3-chloro-4-methoxyphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-6;-   1-(benzo[d][1,3]dioxol-5-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-7;-   1-(3-chloro-5-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-8;-   1-(3,5-bis(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-9;-   1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-10;-   1-(3-(dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-11;-   N-(5-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)-2-methylphenyl)acetamide    II-12;-   1-(3-chloro-4-(dimethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-13;-   N-(2-chloro-4-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)phenyl)acetamide    II-14;-   1-(3-chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)urea    II-15;-   5-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)-2-methylbenzamide    II-16;-   (S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-17;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide    II-18;-   (S)-1-(3-chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-19;-   1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1,3-dimethylurea    II-20;-   1-(3-chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-21;-   1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1-methylurea    II-22;-   3-(1-(((3-((3-chloro-4-methylphenyl)amino)propyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione    II-23;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide    II-24;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-fluorophenyl)acetamide    II-25;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methyl-4-morpholinophenyl)urea    II-26;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methyl-4-(pyrrolidin-1-yl)phenyl)urea    II-27;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide    II-28;-   (S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide    II-29;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)acetamide    II-30;-   1-(3-chloro-4-methylphenyl)-3-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)urea    II-31;-   1-(3-chloro-4-methylbenzyl)-3-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)urea    II-32;-   3-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)propenamide    II-33;-   3-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamide    II-34;-   3-{2-[(3-chloro-4-methylphenylsulfonylamino)methyl]-6-oxo-3-thia-7-azabicyclo[3.3.0]octa-1,4-dien-7-yl}-2,6-piperidinedione    II-35;-   1-(2,6-dichlorobenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ur    II-36;-   1-(2,6-dichlorobenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-37;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2,2-difluoroacetamide    II-38;-   1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)thiourea    II-39;-   1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)urea    II-40;-   4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide    II-41;-   1-(2,6-dichlorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-42;-   1-(2,6-dichlorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-43;-   3-{3-[(3-chloro-4-methylphenylsulfonylamino)methyl]-8-oxo-2-thia-7-azabicyclo[3.3.0]octa-1(5),3-dien-7-yl}-2,6-piperidinedione    II-44;-   1-(3-(dimethylamino)-4-fluorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-45;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-hydroxy-4-methylphenyl)urea    II-46;-   1-(3-(diethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-47;-   1-(3-(dimethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-48;-   1-(3-(dimethylamino)-5-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-49;-   1-(3-(dimethylamino)-5-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-50;-   1-(3-((dimethylamino)methyl)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-51;-   1-(4-(diethylamino)-3-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-52;-   1-(3-((dimethylamino)methyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-53;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-isopropyl-4-methylphenyl)urea    II-54;-   1-(3-(dimethylamino)-4-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-55;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(isopropyl(methyl)amino)phenyl)urea    II-56;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)acetamide    II-57;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methoxy-4-methylphenyl)urea    II-58;-   1-(4-(dimethylamino)-3-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-59;-   1-(3-(dimethylamino)-5-isopropylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-60;-   2-(4-(dimethylamino)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide    II-61;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide    II-62;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(3-isopropyl-4-methoxyphenyl)acetamide    II-63;-   3-(1-(((5-((3-chloro-4-methylphenyl)amino)pentyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione    II-64;-   3-(2-(((3-((3-chloro-4-methylphenyl)amino)propyl)amino)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione    II-65;-   3-(2-(((3-((3-chloro-4-methylphenyl)amino)propyl)amino)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione    II-66;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamide    II-67;-   2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide    II-68;-   1-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)methanesulfonamide    II-69;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-isopropylphenyl)urea    II-70;-   1-(3-(diethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-71;-   1-(3-chloro-4-methylphenyl)-3-((5-(2,5-dioxopyrrolidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-72;-   1-(3-chloro-4-methylphenyl)-3-((5-(3-methyl-2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-73;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-isopropylphenyl)acetamide    II-74;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-methylcyclohexyl)acetamide    II-75;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(3-(piperidin-1-yl)phenyl)acetamide    II-76;-   2-(3-(2-(dimethylamino)ethoxy)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide    II-77;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-morpholinoacetamide    II-78;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)acetamide    II-79;-   2-(4-(2-(dimethylamino)ethoxy)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide    II-80;-   (3-(24(3-(3-(dimethylamino)-4-methylphenyl)ureido)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methyl    D-valinate II-81;-   (3-(24(3-(3-chloro-4-methylphenyl)ureido)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methyl    D-valinate II-82;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-morpholinophenyl)acetamide    II-83;-   4-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide    II-84;-   4-(4-(dimethylamino)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide    II-85;-   4-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-methylbutanamide    II-86;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide    II-87;-   2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(p-tolyl)acetamide    II-88;-   2-amino-2-(3-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide    II-89;-   (S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-90;-   (R)-1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-91;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamide    II-92;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(pyrrolidin-1-yl)phenyl)acetamide    II-93;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-methylbutanamide    II-94;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-methylbutanamide    II-95;-   1-(3-(dimethylamino)-4-ethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-96;-   1-(3-(diethylamino)-4-fluorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-97;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(4-methyl-3-(pyrrolidin-1-yl)phenyl)urea    II-98;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(pyrrolidin-1-yl)phenyl)urea    II-99;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(ethyl(methyl)amino)-4-methylphenyl)urea    II-100;-   4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-methylbutanamide    II-101;-   (2S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamide    II-102;-   (2R)-2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamide    II-103;-   (S)-4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-dimethylbutanamide    II-104;-   di-tert-butyl    ((3-(2-((3-(3-(dimethylamino)-4-methylphenyl)ureido)-methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methyl)    phosphate II-105;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-isopropylphenyl)-3-methylbutanamide    II-106;-   N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(perfluorophenyl)acetamide    II-107;-   2-(dimethylamino)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(2-fluorophenyl)acetamide    II-108;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-phenylbutanamide    II-109;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-phenylthiourea    II-110;-   1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)thiou    II-111;-   2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-propoxyphenyl)acetamide    II-112;-   2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-hydroxyphenyl)acetamide    II-113;-   1-(3-(dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-114;-   4-(4-(dimethylamino)-3-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide    II-115;-   N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(3-fluoro-2-methoxyphenyl)acetamide    II-116;-   4-bromo-2,5-dichloro-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiophene-3-sulfonamide    II-117;-   methyl    5-chloro-3-(N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)sulfamoyl)thiophene-2-carboxylate    II-118;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide    II-119;-   N-(5-(N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)sulfamoyl)-4-methylthiazol-2-yl)acetamide    II-120;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,3,4,5,6-pentafluorobenzenesulfonamide    II-121;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide    II-122;-   1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(2,3,5,6-tetrachlorophenyl)thiourea    II-123;-   4-(tert-butyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)benzenesulfonamide    II-124;-   methyl    3-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)thiophene-2-carboxylate    II-125;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiazole-2-carboxamide    II-126;-   1-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)cyclopropane-1-carboxamide    II-127;-   1-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)methanesulfonamide    II-128;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide    II-129;-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)furan-3-sulfonamide    II-130;-   4-(tert-butyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)benzenesulfonamide    II-131;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-hydroxyacetamide    II-132;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3,3,3-trifluoro-2-hydroxypropanamide    II-133;-   3-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)furan-2-carboxamide    II-134;-   4-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(trifluoromethoxy)benzenesulfonamide    II-135;-   2-chloro-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)thiazole-5-carboxamide    II-136;-   methyl    2-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)thiophene-3-carboxylate    II-137;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(6-morpholinopyridin-3-yl)urea    II-138;-   1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-139;-   N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3,5-dimethylisoxazole-4-carboxamide    II-140;-   N-(5-(N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)sulfamoyl)-4-methylthiazol-2-yl)acetamide    II-141;-   N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2,5-dimethylfuran-3-sulfonamide    II-142;-   5-(N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)sulfamoyl)-2-methoxy-N,N-dimethylbenzamide    II-143;-   N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(propylthio)nicotinamide    II-144;-   1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-phenoxypropyl)urea    II-145; or-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-(4-morpholinophenyl)butanamide    II-146;    or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is:

-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3,3,3-trifluoropropanamide    II-147;-   1-(4-(tert-butyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea    II-148;-   1-(2,3-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-150;-   1-(2,4-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-151;-   1-(2,5-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-152;-   1-([1,1′-biphenyl]-4-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-153;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(4-methoxyphenyl)urea    II-154;-   1-(4-cyanophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-155;-   1-(2,6-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-155;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-phenethylthiourea    II-157;-   1-(2-trifluoromethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-158;-   1-(3-cyanophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-159;-   1-(4-chloro-2-trifluoromethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-160;-   1-(2,4,6-trimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-161;-   1-(3,5-dimethoxyphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea    II-162;-   1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(naphthalen-1-yl)urea    II-163; or-   N-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    II-165;    or an enantiomer, a mixture of enantiomers, a diastereomer, a    mixture of two or more diastereomers, a tautomer, a mixture of two    or more tautomers, or an isotopic variant thereof; or a    pharmaceutically acceptable salt, solvate, hydrate, or prodrug    thereof.

Compounds of Formula (IV)

In one embodiment, provided herein is a compound of Formula (IV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R^(6a), R^(6b), R^(Z), m, and n1 are each as defined herein for Formula(III).

In certain embodiments, R^(Z) is —NR^(7a)R^(8a), wherein R^(7a) andR^(8a) are each as defined herein for Formula (I). In certainembodiments, R^(Z) is —NR^(7a)R^(8a), wherein R^(7a) and R^(8a) are eachindependently H or optionally substituted C₁-C₆ alkyl. In certainembodiments, R^(Z) is —NHCH₃, —NHC₂H₅, —N(CH₃)₂, —N(CH₃)C₂H₅, or—N(C₂H₅)₂. In certain embodiments, R^(Z) is dimethylamino. In certainembodiments, R^(Z) is ring A as defined herein for Formula (I).

In one embodiment, provided herein is a compound of Formula (IVa):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3a), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In another embodiment, provided herein is a compound of Formula (IVb):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3b), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(IVc):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3a), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(IVd):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3d), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(IVe):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3e), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In still another embodiment, provided herein is a compound of Formula(IVf):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3f), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In one embodiment, in any one of Formulae (IVa) to (IVf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) amino, mono-substituted amino, or di-substituted        amino; or (b) C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;

-   -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is independently H or C₁-C₆ alkyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in any one of Formulae (IVa) to (IVf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) mono-substituted amino or di-substituted amino;        or (b) phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is independently H or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3,

In yet another embodiment, in any one of Formulae (IVa) to (IVf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) dimethylamino; or (b) phenyl, naphthyl, thienyl,        pyridyl, piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, propyl, butyl,        hydroxyl-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (IVa) to (IVf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, naphthyl, thienyl, pyridyl,        piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, isopropyl, sec-butyl,        tert-butyl, hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (IVa) to (IVf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, cyanophenyl, fluorophenyl,        chlorophenyl, bromophenyl, methylphenyl,        (1-trifluoromethylethyl)phenyl, trifluoromethylphenyl,        dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl,        isopropylphenyl, sec-butylphenyl, tert-butylphenyl,        (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl,        (1-methylcyclopropyl)phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In still another embodiment, in any one of Formulae (IVa) to (IVf),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,        4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethylethyl)phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methylcyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In one embodiment, provided herein is a compound of Formula (IVg):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In another embodiment, provided herein is a compound of Formula (IVh):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(IVi):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In one embodiment, in any one of Formulae (IVg) to (IVi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) amino, mono-substituted amino, or di-substituted        amino; or (b) C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

-   -    where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;    -   R^(3g) is halogen or C₁-C₆ alkyl;    -   each R^(6a) and R^(6b) is independently H or C₁-C₆ alkyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in any one of Formulae (IVg) to (IVi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) mono-substituted amino or di-substituted amino;        or (b) phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is independently H or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3,

In yet another embodiment, in any one of Formulae (IVg) to (IVi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) dimethylamino; or (b) phenyl, naphthyl, thienyl,        pyridyl, piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, propyl, butyl,        hydroxyl-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (IVg) to (IVi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, naphthyl, thienyl, pyridyl,        piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, isopropyl, sec-butyl,        tert-butyl, hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (IVg) to (IVi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, cyanophenyl, fluorophenyl,        chlorophenyl, bromophenyl, methylphenyl,        (1-trifluoromethylethyl)phenyl, trifluoromethylphenyl,        dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl,        isopropylphenyl, sec-butylphenyl, tert-butylphenyl,        (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl,        (1-methylcyclopropyl)phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In yet another embodiment, in any one of Formulae (IVg) to (IVi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,        4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethylethyl)phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methylcyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In still another embodiment, in Formula (IVg) to (IVi),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl,        3-tert-butylphenyl, 4-tert-butylphenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 3-methoxyphenyl,        4-methoxyphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        2-naphthyl, 5-isopropylthien-2-yl, 4-pyridyl,        4-tert-butylcyclohexyl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is methyl;    -   m is an integer of 1 or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In one embodiment, provided herein is:

-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide    II-18;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide    II-28;-   (S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide    II-29;-   2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2,2-difluoroacetamide    II-38;-   2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide    II-129;-   N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    II-164; or-   N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide    II-165;    or an enantiomer, a mixture of enantiomers, a diastereomer, a    mixture of two or more diastereomers, a tautomer, a mixture of two    or more tautomers, or an isotopic variant thereof; or a    pharmaceutically acceptable salt, solvate, hydrate, or prodrug    thereof.

Compounds of Formula (V)

In one embodiment, provided herein is a compound of Formula (V):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R¹, R²,R^(6a), R^(6b), R^(Z), m, and n1 are each as defined herein for Formula(III).

In another embodiment, provided herein is a compound of Formula (Va):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; R¹, R², R^(6a),R^(6b), R^(Z), m, and n1 are each as defined herein for Formula (III).

In certain embodiments, R^(Z) is —NR^(7a)R^(8a), wherein R^(7a) andR^(8a) are each as defined herein for Formula (I). In certainembodiments, R^(Z) is —NR^(7a)R^(8a), wherein R^(7a) and R^(8a) are eachindependently H or optionally substituted C₁-C₆ alkyl. In certainembodiments, R^(Z) is —NHCH₃, —NHC₂H₅, —N(CH₃)₂, —N(CH₃)C₂H₅, or—N(C₂H₅)₂. In certain embodiments, R^(Z) is dimethylamino. In certainembodiments, R^(Z) is ring A as defined herein for Formula (I).

In one embodiment, provided herein is a compound of Formula (Vb):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3a), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In another embodiment, provided herein is a compound of Formula (Vc):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3a), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(Vd):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3c), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(Ve):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3d), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(Vf):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3e), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In still another embodiment, provided herein is a compound of Formula(IVg):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3f), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In one embodiment, in any one of Formulae (Vb) to (Vg),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) amino, mono-substituted amino, or di-substituted        amino; or (b) C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

-   -    where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is independently H or C₁-C₆ alkyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in any one of Formulae (Vb) to (Vg),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) mono-substituted amino or di-substituted amino;        or (b) phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is independently H or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3,

In yet another embodiment, in any one of Formulae (Vb) to (Vg),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) dimethylamino; or (b) phenyl, naphthyl, thienyl,        pyridyl, piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, propyl, butyl,        hydroxyl-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (Vb) to (Vg),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, naphthyl, thienyl, pyridyl,        piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, isopropyl, sec-butyl,        tert-butyl, hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (Vb) to (Vg),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, cyanophenyl, fluorophenyl,        chlorophenyl, bromophenyl, methylphenyl,        (1-trifluoromethylethyl)phenyl, trifluoromethylphenyl,        dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl,        isopropylphenyl, sec-butylphenyl, tert-butylphenyl,        (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl,        (1-methylcyclopropyl)phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In still another embodiment, in any one of Formulae (Vb) to (Vg),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,        4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethylethyl)phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methylcyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), or R^(3f), if present,        is H;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In one embodiment, provided herein is a compound of Formula (Vh):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In another embodiment, provided herein is a compound of Formula (Vi):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In yet another embodiment, provided herein is a compound of Formula(Vj):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein R², R⁴,R⁵, R^(3g), R^(6a), R^(6b), R^(Z), X, m, p, and n1 are each as definedherein.

In one embodiment, in any one of Formulae (Vh) to (Vj),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) amino, mono-substituted amino, or di-substituted        amino; or (b) C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈        carbocyclyl, or 3 to 10 membered heterocyclyl, each of which is        optionally substituted with one, two, or three substituents        R^(A), wherein each substituent R^(A) is independently (i)        halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a), or —NR^(7d)C(O)R^(11b),        or (ii) phenyl, C₃-C₈ carbocyclyl, or 3 to 10 membered        heterocyclyl, each of which is optionally substituted with one        or more R^(B);    -   R² is H or C₁-C₆ alkyl;    -   R⁴ is H or C₁-C₆ alkyl;    -   R⁵ is H or

where R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each as defined herein;

-   -   R^(3g) is halogen or C₁-C₆ alkyl;    -   each R^(6a) and R^(6b) is independently H or C₁-C₆ alkyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1, or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In another embodiment, in any one of Formulae (Vh) to (Vj),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) mono-substituted amino or di-substituted amino;        or (b) phenyl, naphthyl, thienyl, pyridyl, piperidinyl, or        cyclohexyl, each of which is optionally substituted with one,        two, or three substituents R^(A), wherein each substituent R^(A)        is independently halogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆        alkoxy, C₁-C₆ haloalkyl, —(CH₂)_(t)—NR^(7a)R^(8a),        —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈ carbocyclyl, or 3 to 10        membered heterocyclyl, wherein each of phenyl, 5 to 10 membered        heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 membered heterocyclyl        is optionally substituted with one or more R^(B);    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is independently H or methyl;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 0, 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3,

In yet another embodiment, in any one of Formulae (Vh) to (Vj),

-   -   X is CH₂ or C(═O);    -   R^(Z) is (a) dimethylamino; or (b) phenyl, naphthyl, thienyl,        pyridyl, piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, propyl, butyl,        hydroxyl-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (Vh) to (Vj),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, naphthyl, thienyl, pyridyl,        piperidinyl, or cyclohexyl, each of which is optionally        substituted with one, two, or three substituents R^(A), wherein        each substituent R^(A) is independently cyano, fluoro, chloro,        bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,        dimethylaminomethyl, morpholinylmethyl, isopropyl, sec-butyl,        tert-butyl, hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,        trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl,        hydroxyl, methoxy, dimethylamino, or acetamido;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, 2, or 3.

In yet another embodiment, in any one of Formulae (Vh) to (Vj),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, cyanophenyl, fluorophenyl,        chlorophenyl, bromophenyl, methylphenyl,        (1-trifluoromethylethyl)phenyl, trifluoromethylphenyl,        dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl,        isopropylphenyl, sec-butylphenyl, tert-butylphenyl,        (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl,        (1-methylcyclopropyl)phenyl,        (1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,        (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,        dimethylaminophenyl, acetamidophenyl, difluorophenyl,        dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,        dimethylphenyl, trimethylphenyl, trimethoxyphenyl,        dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,        thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl,        piperidinyl, or tert-butylpiperidinyl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is fluoro or methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In yet another embodiment, in any one of Formulae (Vh) to (Vj),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,        4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethylethyl)phenyl,        4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,        4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl,        4-sec-butylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,        4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,        4-(1-methylcyclopropyl)phenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,        4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,        3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,        4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,        5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl,        piperdin-4-yl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is methyl;    -   each R^(6a) and R^(6b) is H;    -   m is an integer of 0, 1, or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In still another embodiment, in Formula (Vh) to (Vj),

-   -   X is CH₂ or C(═O);    -   R^(Z) is dimethylamino, phenyl, 4-cyanophenyl, 2-fluorophenyl,        3-fluorophenyl, 3-chlorophenyl, 4-trifluoromethylphenyl,        3-tert-butylphenyl, 4-tert-butylphenyl,        4-(1-trifluoromethylcyclopropyl)phenyl, 3-methoxyphenyl,        4-methoxyphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,        3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,        3,5-dimethylphenyl, 2,4,6-trimethylphenyl,        2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,        2-naphthyl, 5-isopropylthien-2-yl, 4-pyridyl,        4-tert-butylcyclohexyl, or 4-tert-butylpiperidin-1-yl;    -   R² is H or methyl;    -   R⁴ is H;    -   R⁵ is H or D-valyloxymethyl;    -   R^(3g) is methyl;    -   m is an integer of 1 or 2;    -   p is an integer of 1 or 2; and    -   n1 is an integer of 0, 1, or 2.

In one embodiment, provided herein is(E)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acrylamideII-149; or an enantiomer, a mixture of enantiomers, a diastereomer, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.

In any embodiments of the compounds described herein, when a substituentis selected from a carbocyclyl (e.g., C₃-C₈ carbocyclyl), it includesC₃-C₈ cycloalkyl. When a substituent is select from 3 to 7 memberedheterocyclyl, it includes 3 to 7 membered monocyclic heterocycle ringswith no double or triple bond within the ring structure.

In certain embodiments, the compound provided herein is formed as apharmaceutically acceptable salt. In certain embodiments, the compoundprovided herein or a pharmaceutically acceptable salt thereof isracemic. In certain embodiments, the compound provided herein or apharmaceutically acceptable salt thereof has an S-configuration at thecarbon atom with an asterisk

In certain embodiments, the compound provided herein or apharmaceutically acceptable salt thereof has an R-configuration at thecarbon atom with an asterisk

In some embodiments, the compound provided herein or a pharmaceuticallyacceptable salt thereof is enriched in one enantiomer over anotherenantiomer, for example, enriched by about 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95%, or 99%, or any value in between. In certainembodiments, the compound provided herein or a pharmaceuticallyacceptable salt thereof is enriched in one diastereomer over anotherdiastereomer, for example, enriched by about 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95%, or 99%, or any value in between. In certainembodiments, the compound provided herein is a pharmaceuticallyacceptable salt. In some embodiments, the compound provided herein or apharmaceutically acceptable salt thereof is a pharmaceuticallyacceptable solvate.

Methods of Treatment/Uses

In certain embodiments, provided herein is a method of treating,ameliorating, or preventing a disease, disorder, or condition associatedwith GSPT1 in a subject, comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound provided herein. In certainembodiments, the disease, disorder, or condition is associated withGSPT1 malfunction. In certain embodiments, the disease, disorder, orcondition is inflammation, fibromyalgia, rheumatoid arthritis,osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis,inflammatory bowel diseases, Crohn's disease, ulcerative colitis,uveitis, inflammatory lung diseases, chronic obstructive pulmonarydisease, Alzheimer's disease, or cancer. In certain embodiments, thedisease, disorder, or condition is cancer. Non-limiting examples ofcancer include breast cancer, melanoma, renal cancer, prostate cancer,colon cancer, lung cancer, bladder cancer, brain cancer, cervicalcancer, head and neck cancer, esophageal and gastric cancers,osteosarcoma, multiple myeloma, leukemia, lymphoma, neuroendocrinecancer, hepatocellular carcinoma, renal cell cancer, pancreatic cancer,thyroid cancer, glioblastoma, ovarian, endometrial cancer, andastrogliosis. In certain embodiments, the disease, disorder, orcondition is a breast cancer, lung cancer, leukemia, lymphoma,hepatocellular carcinoma, gastric cancer, or prostate cancer andastrogliosis. In certain embodiments, the disease, disorder, orcondition is leukemia, acute myelogenous leukemia, acute myeloidleukemia, lymphoma, or hepatocellular carcinoma. In certain embodiments,the subject possesses wild-type GSPT1 or aberrant GSPT1. In certainembodiments, the subject overexpresses GSPT1.

In certain embodiments, provided herein is a method of inhibiting GSPT1activity in a cell, or a method of decreasing a cellular level of GSPT1in a cell, comprising contacting the cell with an effective amount of acompound provided herein or a pharmaceutically acceptable salt thereof.In certain embodiments, the cell is a breast cancer cell, a lung cancercell, a leukemia cell, a lymphoma cell, a hepatocellular carcinoma cell,a gastric cancer cell, or a prostate cancer cell. In certainembodiments, the cell is a leukemia cell, a lymphoma cell, or ahepatocellular carcinoma cell. In certain, the cell possesses wild-typeGSPT1 or aberrant GSPT1, or overexpresses GSPT1.

In certain embodiments, provided herein is a method of treating,ameliorating, or preventing a disease, disorder, or condition associatedwith a protein in a subject, comprising administering to the subject atherapeutically effective amount of a compound provided herein or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound provided herein; wherein the proteinis a cytokine, aiolos, ikaros, helios, or CK1α. In certain embodiments,the protein is a cytokine. In certain embodiments, the cytokine isIL-1β, IL-6, TNFα, or IL-2. In certain embodiments, the cytokine is apro-inflammatory cytokine. In certain embodiments, the protein isaiolos, ikaros, or helios. In certain embodiments, the protein is CK1α.In certain embodiments, the disease, disorder, or condition isinflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatorybowel diseases, Crohn's disease, ulcerative colitis, uveitis,inflammatory lung diseases, chronic obstructive pulmonary disease,Alzheimer's disease, or cancer. In certain embodiments, the disease,disorder, or condition is cancer. In certain embodiments, the disease,disorder, or condition is a leukemia, a lymphoma, or a hepatocellularcarcinoma.

In one embodiment, the subject is a mammalian. In another embodiment,the subject is a human.

In certain embodiments, provided herein is a method of modulating (suchas inhibiting or stimulating) protein activity, comprising contacting acell with a compound provided herein or a pharmaceutically acceptablesalt thereof; wherein the protein is a cytokine, aiolos, ikaros, helios,or CK1α. In certain embodiments, the method is to inhibit a cytokineactivity, wherein the cytokine is a pro-inflammatory cytokine selectedfrom a group consisting of IL-1β, IL-6, and TNFα. In certainembodiments, the method is to stimulate cytokine activity, wherein thecytokine is an anti-inflammatory cytokine, such as IL-2. In certainembodiments, the method is to inhibit aiolos activity. In certainembodiments, the method is to inhibit ikaros activity. In certainembodiments, the method is to inhibit helios activity. In certainembodiments, the method is to inhibit CK1α activity.

In certain embodiments, provided herein is a method for treating,ameliorating, or preventing a skin disorder, disease, or condition in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising acompound provided herein. In certain embodiments, the skin disorder isskin cancer.

In certain embodiments, a compound provided herein is in the form of apharmaceutically acceptable salt, solvate, active metabolite, tautomer,or prodrug thereof. In certain embodiments, the pharmaceuticalcomposition provided herein contains at least one pharmaceuticallyacceptable inactive ingredient. The pharmaceutical composition can beformulated for intravenous injection, subcutaneous injection, oraladministration, buccal administration, inhalation, nasal administration,topical administration, transdermal administration, ophthalmicadministration, or otic administration. The pharmaceutical compositioncan be in the form of a tablet, a pill, a capsule, a liquid, aninhalant, a nasal spray solution, a suppository, a suspension, a gel, acolloid, a dispersion, a solution, an emulsion, an ointment, a lotion,an eye drop, or an ear drop.

The pharmaceutical composition provided herein can further comprise anadditional therapeutically active agent other than a compound providedherein. Such a agent can include, but are not limited to, ananti-inflammatory agent, anti-cancer agent, immunostimulatory agent, orimmunosuppressive agent.

Pharmaceutical Compositions

In certain embodiments, provided herein is a pharmaceutical compositioncomprising a compound provided herein or a pharmaceutically acceptablesalt thereof; and a pharmaceutically acceptable excipient.

As used herein, an “excipient” refers to an essentially inert substancethat is added to a pharmaceutical composition to provide, withoutlimitation, bulk, consistency, stability, binding ability, lubrication,disintegrating ability etc., to the composition. For example,stabilizers such as anti-oxidants and metal-chelating agents areexcipients. Excipients also include ingredients in a pharmaceuticalcomposition that lack appreciable pharmacological activity but may bepharmaceutically necessary or desirable. For example, to increase thebulk of a potent drug which mass is too small for manufacture and/oradministration. It may also be a liquid for the dissolution of a drug tobe administered by injection, ingestion, or inhalation. For example, abuffered aqueous solution, such as, without limitation, phosphatebuffered saline that mimics the pH and isotonicity of the human blood.

The pharmaceutical compositions described herein can be administered toa human patient per se, or in pharmaceutical compositions where they aremixed with other active ingredients, as in combination therapy, orexcipients, or combinations thereof. Proper formulation is dependentupon the route of administration chosen. Techniques for formulation andadministration of the compounds described herein are known to thoseskilled in the art.

Multiple techniques of administering a compound, salt and/or compositionexist in the art including, but not limited to, oral, rectal, pulmonary,topical, aerosol, injection, infusion and parenteral delivery, includingintramuscular, subcutaneous, intravenous, intramedullary injections,intrathecal, direct intraventricular, intraperitoneal, intranasal andintraocular injections. In certain embodiments, a compound providedherein or a pharmaceutically acceptable salt thereof, or apharmaceutical composition thereof is administered orally or topically.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may, for example, comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. The pack or dispensermay also be accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such a notice, for example, may be the labeling approvedby the U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. Compositions that can include a compound and/orsalt described herein formulated in a compatible pharmaceuticalexcipient may also be prepared, placed in an appropriate container, andlabeled for treatment of an indicated condition.

The disclosure will be further understood by the following non-limitingexamples.

EXAMPLES

As used herein, the symbols and conventions used in these processes,schemes, and examples, regardless of whether a particular abbreviationis specifically defined, are consistent with those used in thecontemporary scientific literature, for example, the Journal of theAmerican Chemical Society, the Journal of Medicinal Chemistry, or theJournal of Biological Chemistry.

For all of the following examples, standard work-up and purificationmethods known to those skilled in the art can be utilized. Unlessotherwise indicated, all temperatures are expressed in ° C. (degreesCentigrade). All reactions are conducted at room temperature unlessotherwise specified. Synthetic methodologies illustrated herein areintended to exemplify the applicable chemistry through the use ofspecific examples and are not indicative of the scope of the disclosure.

The starting materials (e.g., compound 3) used in the following exampleswere commercially available or prepared, for example, according to theprocedures described in US 2019/0322683 A1, US 2019/0365775, and US2020/0009120 A1, the disclosure of each of which is incorporated hereinby reference in its entirety.

Example 1 Compound I-1:2-(4-(Tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide

Compound I-1 was synthesized as shown in Scheme 1.

To a solution of 2-(4-(tert-butyl)phenyl)-2-oxoacetic acid 1 (3.38 g, 16mmol) in DCM (25 mL) at RT was added oxalyl chloride (4.17 g, 33 mmol)and one drop of DMF. After stirring at RT for 18 h, the reaction wasconcentrated to give 2-(4-(tert-butyl)phenyl)-2-oxoacetyl chloride 2(3.8 g, 100% yield) as an oil.

To a solution of3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione3 (2.0 g, 5.2 mmol) in DCM (20 mL) was added TEA (1.58 g, 15.6 mmol) and2-(4-(tert-butyl)phenyl)-2-oxoacetyl chloride 2 (1.4 g, 6.3 mmol). Afterstirring at RT for 3 h, the mixture was concentrated and the residue waspurified using silica gel eluting with DCM/MeOH (10:1) to give compoundI-1 (1.1 g) in 45% yield. MS (ESI) m/z: 468.1 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d6) δ 10.98 (s, 1H), 9.57 (t, J=6.0 Hz, 1H), 7.94-7.92 (m, 3H),7.60 (d, J=8.4 Hz, 1H), 5.05-5.01 (m, 1H), 4.59 (d, J=6.0 Hz, 2H),4.37-4.22 (m, 4H), 3.67 (d, J=5.6 Hz, 2H), 2.91-2.85 (m, 1H), 2.67-2.57(m, 1H), 2.34-2.25 (m, 1H), 2.02-1.97 (m, 1H), 1.31 (s, 9H).

Example 2 Compound I-2:2-(4-(Tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide

Compound I-2 was synthesized as shown in Scheme 2.

To a solution of methyl 4-cyano-2-methylbenzoate 4 (4.00 g, 22.8 mmol)in CCl₄ (150 mL) at RT was added NBS (4.88 g, 27.4 mmol), and thesuspension was heated at 80° C. for 5 min. AIBN (1.88 g, 11.4 mmol) wasadded, and the mixture was heated at 80° C. for 16 h and then cooled toRT and filtered. The filtrate was concentrated and the residue waspurified using silica gel eluting with EA/PE from 0% to 5% to givemethyl 2-(bromomethyl)-4-cyanobenzoate 5 (3.84 g, 67% yield).

To a solution of methyl 2-(bromomethyl)-4-cyanobenzoate 5 (729 mg, 2.7mmol) and 3-aminopiperidine-2,6-dione (532 mg, 3.2 mmol) in DMF (12 mL)at RT was added TEA (1.2 mL, 8.1 mmol). The reaction mixture was heatedat 85° C. for 4 h and then concentrated. The residue was purified usingsilica gel eluting with DCM/MeOH (100:1 to 50:1) to afford2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile 6 (320 mg)in 44% yield. MS (ESI) m/z: 270.0 [M+H]⁺; ¹H NMR (300 MHz, DMSO-d6) δ11.03 (s, 1H), 8.16 (s, 1H), 7.99 (d, J=7.8 Hz, 1H), 7.91 (d, J=7.8 Hz,1H), 5.18-5.12 (m, 1H), 4.58-4.39 (m, 2H), 2.92-2.62 (m, 1H), 2.57 (d,J=2.1 Hz, 1H), 2.45-2.40 (m, 1H), 2.05-2.00 (m, 1H).

To a solution of2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile 6 (320 mg,1.18 mmol) in MeOH (16 mL) at RT was added Raney Ni (180 mg), followedby the addition of di-tert-butyl dicarbonate (514 mg, 2.36 mmol). Thesuspension was stirred at RT for 14 h under H₂, and then filtered andconcentrated. The residue was purified using silica gel eluting withDCM/MeOH (100:1 to 50:1) to give tert-butyl((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate 7(280 mg) in 63% yield. MS (ESI) m/z: 374.1 [M+H]⁺.

To a solution of tert-butyl((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-carbamate 7(160 mg, 0.42 mmol) in DCM (6 mL) at RT was added TFA (1.5 mL). Themixture was stirred for 3 h and then concentrated to give3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione TFA 8 (190mg). MS (ESI) m/z: 274.1 [M+H]⁺.

To a solution of 2-(4-(tert-butyl)phenyl)-2-oxoacetyl chloride 2 (109 mgcrude, 0.485 mmol) in DCM (5 mL) at RT was added TEA (98 mg, 0.97 mmol),followed by the addition of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 8 (132 mg,0.485 mmol). The mixture was stirred at RT for 3 h and thenconcentrated. The residue was purified using prep-HPLC eluting withACN/H₂O (0.1% TFA) from 10% to 95% to give compound I-2 (35 mg) in 16%yield. MS (ESI) m/z: 462.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s,1H), 9.51 (t, J=6.0 Hz, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.0 Hz,1H), 7.62 (d, J=8.4 Hz, 3H), 7.48 (d, J=7.6 Hz, 1H), 5.11 (dd, J=4.8,13.2 Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.49-4.31 (m, 2H), 2.96-2.88 (m,1H), 2.66-2.57 (m, 1H), 2.41-2.32 (m, 1H), 2.02-1.99 (m, 1H), 1.31 (s,9H).

Example 3 Compound I-3:N-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide

Compound I-3 was synthesized as shown in Scheme 3.

To a solution of 1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene 10(368 mg, 1.39 mmol) in 1,4-dioxane (10 mL) at RT was addedtributyl(1-ethoxyvinyl)stannane (762 mg, 2.11 mmol) and Pd(PPh₃)₄(321mg, 0.278 mmol). The mixture was purged with N₂ and then stirred at 100°C. overnight. The mixture was filtered and concentrated. After theresidue was dissolved in THF, HCl (1N) was added at RT and the mixturewas stirred for 10 min. The mixture was washed with NaHCO₃(aq.) andextracted with EA. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The crude product waspurified using silica gel column eluting with DCM/MeOH (10:1) to give1-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)ethanone 11 (270 mg) in 76%yield.

To a solution of 1-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)ethanone 11(165 mg, 0.724 mmol) in pyridine (8 mL) at RT was added SeO₂ (160.6 mg,1.447 mmol). After stirring at 90° C. for 2 h, the mixture wasconcentrated, diluted with water, and extracted with EA. The combineorganic layers were washed with HCl (2N), dried over Na₂SO₄, filtered,and concentrated to afford2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid 12 (150mg), which was used in the next step without further purification.

To a solution of2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid 12 (150 mgcrude, 0.581 mmol) in DCM (8 mL) at RT was added oxalyl chloride (147.6mg, 1.163 mmol) and DMF (2 drops). The mixture was stirred at RT for 1 hand then concentrated to afford2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetyl chloride 13(158 mg), which was used in the next step without further purification.

To a solution of3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione3 (80 mg, 0.286 mmol) in DCM (8 mL) at 0° C. was added Et₃N (57.9 mg,0.573 mmol). After stirring for 2 min,2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetyl chloride 13(158 mg crude, 0.573 mmol) was added and the mixture was stirred at RTfor 2 h. After concentration, the residue was purified by prep-HPLCeluting with ACN/H₂O (0.1% TFA) from 10% to 95% to afford compound I-3(33.6 mg, 23% yield). MS (ESI) m/z: 520.0 [M+H]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 10.98 (s, 1H), 9.62 (t, J=5.6 Hz, 1H), 8.02-7.65 (m, 5H),5.03 (dd, J=5.2 Hz, 13.6 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H), 4.33 (q,J=15.6 Hz, 2H), 2.92-2.84 (m, 1H), 2.61-2.56 (m, 1H), 2.32-2.28 (m, 1H),2.01-1.97 (m, 1H), 1.42-1.39 (m, 2H), 1.23-1.20 (m, 2H).

Example 4 Compound I-4:N-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide

Compound I-4 was synthesized as shown in Scheme 4.

To a solution of ethyl 2-(5-bromothiophen-2-yl)-2-oxoacetate 15 (400 mg,1.520 mmol) in toluene/H₂O (10 mL:1 mL) at RT was added4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (332 mg, 1.98mmol) and K₃PO₄ (967 mg, 4.56 mmol). After the mixture was purged withN₂, Pd(PPh₃)₂Cl₂ (214 mg, 0.304 mmol) was added, and the mixture wasstirred at 100° C. for 16 h and then cooled to RT. The mixture wasfiltered and the filtrate was concentrated. The residue was purifiedusing silica gel eluting with EA/PE from 0% to 9% to give ethyl2-oxo-2-(5-(prop-1-en-2-yl)thiophen-2-yl)acetate 16 (125 mg) in 38%yield.

To a solution of ethyl 2-oxo-2-(5-(prop-1-en-2-yl)thiophen-2-yl)acetate16 (125 mg, 0.558 mmol) in THF (6 mL) at RT was added Pd/C (100 mg). Themixture was degassed and purged with H₂ several times. The mixture wasstirred at RT for 18 h and then filtered and concentrated. The crudeproduct was purified using silica gel eluting with EA/PE from 0% to 9%to give ethyl 2-(5-isopropylthiophen-2-yl)-2-oxoacetate 17 (72 mg) in57% yield.

To a solution of ethyl 2-(5-isopropylthiophen-2-yl)-2-oxoacetate 17 (72mg, 0.318 mmol) in EtOH (4 mL) was added NaOH (aq., 5 M). The mixturewas stirred at RT for 1 h and then concentrated. The residue wasacidified with HCl (4 N) to pH=3 and extracted with EA. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated togive 2-(5-isopropylthiophen-2-yl)-2-oxoacetic acid 18 (63 mg), which wasused in next step without further purification.

To a solution of 2-(5-isopropylthiophen-2-yl)-2-oxoacetic acid 18 (63mg, 0.32 mmol) in DCM (5 mL) at RT was added oxalyl chloride (80.9 mg,0.637 mmol) and DMF (2 drops). The resulting mixture was stirred at RTfor 1 h and then concentrated to give2-(5-isopropylthiophen-2-yl)-2-oxoacetyl chloride 19 (77.5 mg), whichwas used in the next step without further purification.

To a solution of3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione3 (50 mg, 0.179 mmol) in DCM (5 mL) at 0° C. was added TEA (36.2 mg,0.358 mmol). After 2 min, 2-(5-isopropylthiophen-2-yl)-2-oxoacetylchloride 19 (77.5 mg crude, 0.358 mmol) was added, and the mixture wasstirred at RT for 1.5 h. After concentration, the residue was dilutedwith water and extracted with EA. The combined organic layers wereconcentrated and purified using prep-HPLC eluting with ACN/H₂O (0.1%TFA) from 10% to 95% to afford compound I-4 (27 mg, 33% yield). MS (ESI)m/z: 460.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H), 9.62 (t,J=8.0 Hz, 1H), 8.06-7.91 (m, 2H), 7.11 (s, 1H), 5.04-5.00 (m, 1H),4.53-4.51 (m, 2H), 4.35 (q, J=15.6 Hz, 44 Hz, 2H), 2.92-2.83 (m, 1H),2.31-2.25 (m, 2H), 1.99-1.96 (m, 2H), 1.31 (d, J=6.4 Hz, 6H).

Example 5 Compound I-5:N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide

Compound I-5 was synthesized as shown in Scheme 5.

To a solution of3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 8 (80 mg,0.258 mmol) in DCM (4 mL) at 0° C. was added TEA (52.2 mg, 0.516 mmol).After stirring for 2 min,2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetyl chloride 13(71.3 mg, 0.258 mmol) was added and the mixture was stirred at RT for 2h. After concentration, the residue was purified using prep-HPLC elutingwith ACN/H₂O (0.1% TFA) from 10% to 95% to afford compound I-5 (16.1 mg)in 12% yield. MS (ESI) m/z: 514.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ10.98 (s, 1H), 9.57 (t, J=6.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.74-7.48 (m,7H), 5.13-5.09 (m, 1H), 4.59-4.57 (m, 2H), 4.49-4.31 (m, 2H), 2.95-2.87(m, 1H), 2.63-2.58 (m, 1H), 2.45-2.38 (m, 1H), 2.03-1.99 (m, 1H),1.43-1.40 (m, 2H), 1.24-1.21 (m, 2H).

Example 6 Compound I-28:2-(4-(Tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide

Compound I-28 was synthesized as shown in Scheme 6.

To a solution of methyl 3-bromo-2-methylbenzoate 20 (22.9 g, 10 mmol) inCCl₄ (200 mL) was added NBS (21.4 g, 12 mmol) and AIBN (1.64 g, 1 mmol).The mixture was stirred at 85° C. overnight, and then concentrated andpurified using silica gel eluting with PE/EA (10:1) to give methyl3-bromo-2-(bromomethyl)benzoate 21 (24 g) in 78% yield.

To a solution of methyl 3-bromo-2-(bromomethyl)benzoate 21 (6.0 g, 19.5mmol) in ACN (60 mL) was added 3-aminopiperidine-2,6-dione HCl salt (3.8g, 23.4 mmol) and DIEA (12.5 g, 97.4 mmol). The mixture was stirred at90° C. overnight, and then cooled to 40° C., filtered, and washed withtert-butyl methyl ether to give3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 22 (5.5 g) in 87%yield. MS (ESI) m/z: 323.0, 325.0 [M+H]⁺.

To a solution of 3-(4-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione 22(1.5 g, 4.64 mmol) in DMF (10 mL) was added Zn(CN)₂ (0.54 g, 4.64 mmol),dppf (0.52 g, 0.93 mmol), and Pd₂(dba)₃ (0.44 g, 0.46 mmol). The mixturewas heated at 150° C. for 2 h under microwave, and then concentrated andpurified using silica gel eluting with DCM/MeOH from 50:1 to 30:1 togive 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-carbonitrile 23 (990mg) in 79% yield. MS (ESI) m/z: 270.0 [M+H]⁺.

To a solution of2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-4-carbonitrile 23 (0.3 g,1.1 mmol) in MeOH (20 mL) was added Boc₂O (365 mg, 1.7 mmol) and RaneyNi (0.05 mg). The suspension was stirred under H₂ for 48 h. The mixturewas filtered then the filtrate was concentrated and purified usingsilica gel eluting with DCM/MeOH from 50:1 to 30:1 to give tert-butyl((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)carbamate 24(110 mg) in 26% yield. MS (ESI) m/z: 374.1 [M+H]⁺.

To a solution of 2-(4-(tert-butyl)phenyl)-2-oxoacetic acid (206 mg, 1.0mmol) in dioxane (5 mL) at 0° C. was added SOCl₂(1.19 g, 10 mmol), andthe mixture was stirred at 90° C. for 3 h and then concentrated to give2-(4-(tert-butyl)phenyl)-2-oxoacetyl chloride 2 (crude).

To a solution of tert-butyl((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)carbamate 24(110 mg, 0.42 mmol) in DCM (3 mL) at 0° C. was added TFA (1 mL). Themixture was stirred for 2 h and then concentrated. The residue (compound25) (100 mg) was dissolved in DCM (5 mL) and cooled to 0° C. and thenTEA (59 mg, 0.59 mmol) was added. The mixture was stirred at 0° C. for 5min and then a solution of 2-(4-(tert-butyl)phenyl)-2-oxoacetyl chloride2 (1.0 mmol, crude) in DCM (5 mL) was added. The mixture was stirred atRT overnight and then concentrated and purified by prep-HPLC using 0.1%TFA in water and 0.1% TFA in ACN with a gradient of 95% to 5% in 0.1%TFA water to afford compound I-28 (50 mg) in 37% yield. MS (ESI) m/z:462.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.03 (s, 1H), 9.49 (s, 1H),7.92 (d, J=7.6 Hz, 2H), 7.68-7.53 (m, 5H), 5.16 (dd, J=5.2, 13.2 Hz,1H), 4.60-4.42 (m, 4H), 2.93-2.89 (m, 1H), 2.67-2.59 (m, 1H), 2.37-2.33(m, 1H), 2.05-2.01 (m, 1H), 1.31 (s, 9H).

Example 7 Compound I-32:2-(4-(Tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-2-oxoacetamide

Compound I-32 was synthesized as shown in Scheme 7.

To a solution of 5-bromoisobenzofuran-1,3-dione 30 (2.0 g, 8.8 mmol) inAcOH (25 mL) was added 3-aminopiperidine-2,6-dione (1.4 g, 8.8 mmol) andsodium acetate (1.4 g, 17.6 mmol). The mixture was stirred at 120° C.for 5 h and then concentrated. The residue was washed with H₂O, MeOH,and DCM to give 5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione31 (2.7 g) in 90% yield. MS (ESI) m/z: 359.0 [M+Na]⁺.

To a solution of5-bromo-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione 31 (1.0 g, 3.0mmol) in 1-methyl-2-pyrrolidinone (8 mL) was added CuCN (0.8 g, 9.0mmol). The mixture was stirred at 180° C. for 2 h under microwave andthen filtered. The filtrate was diluted with H₂O and extracted with EA.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was triturated with MeOH/DCM(1:10) to give2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbonitrile 32 (600mg) in 71% yield. MS (ESI) m/z: 306.0 [M+Na]⁺.

To a solution of2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbonitrile 32 (0.21g, 0.75 mmol) in MeOH (20 mL) was added Boc₂O (0.24 mg, 1.12 mmol) andRaney Ni (0.06 mg). The mixture was stirred under H₂ for 2 d and thenfiltered, and the filtrate was concentrated. The residue was purifiedusing silica gel eluting with DCM/MeOH from 50:1 to 30:1 to givetert-butyl((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)carbamate33 (80 mg) in 28% yield. MS (ESI) m/z: 405.2 [M+NH₄ ⁺].

To a solution of tert-butyl((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)carbamate33 (80 mg, 0.20 mmol) in DCM (3 mL) was added TFA (1 mL). The mixturewas stirred for 1 h and then concentrated and triturated with methyltert-butyl ether to give5-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione TFAsalt 34 (80 mg, crude). MS (ESI) m/z: 288.0 [M+H]⁺.

To a solution of5-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione TFAsalt 34 (80 mg) in DCM (5 mL) at 0° C. was added TEA (42 mg, 0.42 mmol),followed by addition of 2-(4-(tert-butyl)phenyl)-2-oxoacetyl chloride 2(0.21 mmol). The mixture was stirred at RT overnight and thenconcentrated. The residue was purified by prep-HPLC using conditions toafford compound I-32. MS (ESI) m/z: 476.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 400MHz) δ11.11 (s, 1H), 9.58 (t, J=6.4 Hz, 1H), 7.95-7.82 (m, 5H), 7.61 (d,J=8.4 Hz, 2H), 5.16 (dd, J=5.2, 12.8 Hz, 1H), 4.64 (d, J=6.4 Hz, 2H),2.90-2.86 (m, 1H), 2.67-2.52 (m, 2H), 2.08-2.04 (m, 1H), 1.31 (s, 9H).

Example 8 Compound I-38:2-(4-(Tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)methyl)-2-oxoacetamide

Compound I-38 was synthesized as shown in Scheme 8.

To a solution of methyl 2-bromo-6-methylbenzoate 35 (5.0 g, 21.8 mmol)in DMF (40 mL) was added CuCN (2.35 g, 26.2 mmol) and CuI (415.7 mg,2.18 mmol). The mixture was stirred at 130° C. for 16 h under N₂ andthen cooled 20° C., diluted with methyl tert-butyl ether (30 mL), andfiltered. The filtrate was diluted with H₂O (20 mL) and extracted withmethyl tert-butyl ether (30 mL×2). The combined organic layers wereconcentrated and the residue was purified using silica gel eluting withEA in PE from 2% to 10% to give methyl 2-cyano-6-methylbenzoate 36 (2.8g) in 73% yield.

To a solution of methyl 2-cyano-6-methylbenzoate 36 (2.8 g, 15.98 mmol)in CCl₄ (30 mL) was added NBS (2.84 g, 15.98 mmol) and2,2′-azoisobutyronitrile (787 mg, 4.79 mmol). The mixture was stirred at85° C. for 16 h and then cooled to RT, filtered, and concentrated. Theresidue was purified using silica gel eluting with EA in PE from 10% to20% to give methyl 2-(bromomethyl)-6-cyanobenzoate 37 (3.0 g, 74%yield).

To a solution of methyl 2-(bromomethyl)-6-cyanobenzoate 37 (1.25 g, 4.92mmol) in DMF (20 mL) was added 3-aminopiperidine-2,6-dione hydrochloride(971.7 mg, 5.90 mmol) and TEA (1.49 g, 14.8 mmol). The mixture wasstirred at 85° ° C. for 16 h and then concentrated. The residue wastriturated with ACN to give2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-4-carbonitrile 38 (1.0 g)in 75% yield. MS (ESI) m/z: 270.1 [M+H]⁺.

To a solution of2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindoline-4-carbonitrile 38 (500 mg,1.86 mmol) in MeOH (20 mL) was added di-tert-butyl pyrocarbonate (607.92mg, 2.79 mmol) and Raney Ni (100 mg). The mixture was stirred under H₂overnight and then filtered and concentrated. The residue was purifiedusing silica gel eluting with EA in PE from 50% to 100% and then elutingwith MeOH/DCM (1:10) to give tert-butyl((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)methyl)carbamate 39(360 mg) in 52% yield. MS (ESI) m/z: 318.1 [M-56]⁺.

To a solution of tert-butyl((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)methyl)carbamate 39(110 mg, 0.295 mmol) in DCM (10 mL) was added TFA (2 mL). The mixturewas stirred at 20° C. for 2 h and then concentrated to give3-(7-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 40 (80 mg,crude).

To a solution of3-(7-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 40 (80.0mg, crude) in DMF (20 mL) was added 2-(4-(tert-butyl)phenyl)-2-oxoaceticacid 1 (60.4 mg, 0.293 mmol), HOBt (59.3 mg, 0.439 mmol), EDCI (84.2 mg,0.439 mmol), and DIEA (113.5 mg, 0.878 mmol). The mixture was stirred at20° C. for 16 h and then diluted with H₂O and extracted with DCM. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by prep-HPLC to afford compoundI-38 (24.9 mg) in 18% yield. MS (ESI) m/z: 462.2 [M+H]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 11.00 (s, 1H), 9.37 (t, J=6.0 Hz, 1H), 7.96 (d, J=8.4Hz, 2H), 7.64-7.60 (m, 3H), 7.52 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.2 Hz,1H), 5.13 (dd, J=4.8, 13.2 Hz, 1H), 4.98 (d, J=5.6 Hz, 2H), 4.49-4.32(m, 2H), 2.92-2.87 (m, 1H), 2.63-2.59 (m, 1H), 2.43-2.39 (m, 1H),2.02-1.99 (m, 1H), 1.31 (s, 9H).

Example 9 Compound I-47:2-(4-(Tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-N-methyl-2-oxoacetamide

Compound I-47 was synthesized as shown in Scheme 9.

To a solution of methyl 3-bromo-2-(bromomethyl)benzoate 21 (4.10 g, 13.3mmol, crude) in DMF (30 mL) was added tert-butyl4,5-diamino-5-oxopentanoate (3.19 g, 13.31 mmol) and K₂CO₃ (7.62 g, 75mmol). The mixture was stirred for 20 min and then heated to 50° C. for2 h and heated to 80° C. for 1 h. The solution was cooled to RT, dilutedwith H₂O, and extracted with EA. The combined organic layers were washedwith brine, dried over Na₂SO₄, filtered, and concentrated. The residuewas triturated with methyl tert-butyl ether to give tert-butyl5-amino-4-(4-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate 41 (2.44 g) in46% yield.

To a solution of tert-butyl5-amino-4-(4-bromo-1-oxoisoindolin-2-yl)-5-oxopentanoate 41 (1.24 g,3.12 mmol) in DMF (10 mL) was added Zn(CN)₂ (263 mg, 2.24 mmol),Pd₂(dba)₃ (295 mg, 0.32 mmol), and dppf (344 mg, 0.62 mmol). The mixturewas heated at 150° C. under microwave for 2 h and then concentrated. Theresidue was purified using silica gel eluting with EA in PE from 30% to100% to give tert-butyl5-amino-4-(4-cyano-1-oxoisoindolin-2-yl)-5-oxopentanoate 42 (754 mg) in70% yield.

To a solution of tert-butyl5-amino-4-(4-cyano-1-oxoisoindolin-2-yl)-5-oxopentanoate 42 (754 mg,2.19 mmol) in AcOH/pyridine/H₂O (6 mL/12 mL/6 mL) was added NaH₂PO₂ (962mg, 10.93 mmol) and Raney Ni (0.4 g). The mixture was stirred for 3 hand then filtered, and the filtrate was extracted with EA. The combinedorganic layers were washed with 1N HCl, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified using silica gel eluting with EAin PE from 30% to 100% and give tert-butyl5-amino-4-(4-formyl-1-oxoisoindolin-2-yl)-5-oxopentanoate 43 (426 mg) in55% yield.

To a solution of tert-butyl5-amino-4-(4-formyl-1-oxoisoindolin-2-yl)-5-oxopentanoate 43 (426 mg,1.23 mmol) in DCM (25 mL) was added methylamine (192 mg, 6.19 mmol) andNaBH(OAc)₃ (1.31 g, 6.19 mmol). The mixture was stirred overnight andthen NaBH₃CN (155 mg, 2.47 mmol) was added. The mixture was stirred for1 h and then concentrated. The residue was purified using silica geleluting with EA in PE from 50% to 100% to give tert-butyl5-amino-4-(4-((methylamino)methyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate44 (200 mg) in 45% yield.

To a solution of tert-butyl5-amino-4-(4-((methylamino)methyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate44 (200 mg, 0.55 mmol) in DCM (10 mL) was added TEA (0.15 mL), followedby addition of a solution of 2-(4-(tert-butyl)phenyl)-2-oxoacetylchloride 2 (204 mg, crude) in DCM (4 mL). The mixture was stirred for 1h, and then diluted with H₂O and extracted with DCM. The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The residue was purified using silica gel eluting with EAin PE from 30% to 90% to give tert-butyl5-amino-4-(4-((2-(4-(tert-butyl)phenyl)-N-methyl-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate45 (132 mg) in 43% yield.

To a solution of tert-butyl5-amino-4-(4-((2-(4-(tert-butyl)phenyl)-N-methyl-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate45 (132 mg, 0.24 mmol) in DCM (6 mL) was added TFA (53.6 mg, 0.47 mmol).The mixture was stirred for 1 h and then concentrated. The residue waspurified by prep-TLC eluting with EA in PE from 30% to 100% to give5-amino-4-(44(2-(4-(tert-butyl)phenyl)-N-methyl-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-5-oxopentanoicacid 46 (94 mg) in 79% yield.

To a solution of5-amino-4-(4-((2-(4-(tert-butyl)phenyl)-N-methyl-2-oxoacetamido)-methyl)-1-oxoisoindolin-2-yl)-5-oxopentanoicacid 46 (94 mg, 0.20 mmol) in ACN (6 mL) was added CDI (118 mg, 0.73mmol). The mixture was stirred at 95° C. for 1.5 h and thenconcentrated. The residue was purified by prep-HPLC to afford compoundI-47 (20.4 mg) in 23% yield. MS (ESI) m/z: 476.1 [M+H]⁺; ¹HNMR (DMSO-d₆,400 MHz) δ 11.02 (d, J=14.0 Hz, 1H), 7.85-7.44 (m, 7H), 5.20-5.08 (m,1H), 4.80 (s, 1H), 4.56-4.26 (m, 3H), 2.99-2.85 (m, 4H), 2.66-2.59 (m,1H), 2.51-2.41 (m, 1H), 2.30-1.97 (m, 1H), 1.26 (d, J=10.0 Hz, 9H).

Example 10 Compound I-49:(2R)-(3-(4-((2-(4-(Tert-butyl)phenyl)-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-amino-3-methylbutanoate

Compound I-49 was synthesized as shown in Scheme 10.

To a solution of (R)-2-(((benzyloxy)carbonyl)amino)-3-methylbutanoicacid 50 (0.9 g, 3.6 mmol) in DCM/H₂O (10 mL/1 mL) at 0° C. was addedNaHCO₃(1.2 g, 14.4 mmol), followed by addition of Bu₄NHSO₄ (122 mg, 0.1mmol). After 10 min, chloromethyl sulfochloridate (0.70 g, 4.32 mmol)was added. The mixture was stirred for 4 h. The mixture was diluted withH₂O and extracted with DCM. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated. The residue was purified usingsilica gel eluting with MeOH in DCM from 0% to 1% to give(R)-chloromethyl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 51(0.83 g) in 77% yield. MS (ESI) m/z: 300[M+H]⁺.

To a solution of (R)-chloromethyl2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 51 (232 mg, 0.776 mmol)in ACN (5 mL) was added sodium iodide (140 mg, 0.931 mmol). The mixturewas stirred overnight and then filtered, and the filtrate wasconcentrated. The residue was purified using silica gel eluting with EAin PE from 0% to 10% to give (R)-iodomethyl2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 52 (250 mg) in 83%yield. MS (ESI) m/z: 392 [M+H]⁺.

To a solution of tert-butyl((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)carbamate 24(132 mg, 0.355 mmol) in DMF (4 mL) at 0° C. was added sodium hydride (17mg, 0.71 mmol). The mixture was stirred at RT for 30 min and then(R)-iodomethyl 2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate (250 mg,0.639 mmol) 52 was added. The mixture was stirred at RT for 1 h, andthen diluted with H₂O and extracted with DCM. The combined organiclayers were dried over Na₂SO₄, filtered, and concentrated. The residuewas purified using silica gel eluting with MeOH in DCM from 0% to 5% togive(2R)-(3-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 53 (165 mg) in 36%yield. MS (ESI) m/z: 637 [M+H]⁺.

To a solution of(2R)-(3-(4-(((tert-butoxycarbonyl)amino)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 53 (165 mg, 0.259 mmol)in DCM (4 mL) was added TFA (1 mL). The mixture was stirred for 2 h andthen concentrated to give(2R)-(3-(4-(aminomethyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate TFA salt 54 (139 mg,crude). MS (ESI) m/z: 537 [M+H]⁺.

To a solution of(2R)-(3-(4-(aminomethyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 54 (139 mg, 0.26 mmol)in DCM (5 mL) was added TEA (65 mg, 0.65 mmol), followed by addition of2-(4-(tert-butyl)phenyl)-2-oxoacetyl chloride 2 (87.5 mg, 0.39 mmol).The mixture was stirred for 4 h and then concentrated. The residue waspurified using silica gel eluting with MeOH in DCM from 0% to 8% to give(2R)-(3-(4-((2-(4-(tert-butyl)phenyl)-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 55 (125 mg, 67% yield).MS (ESI) m/z: 725 [M+H]⁺.

To a solution of(2R)-(3-(4-((2-(4-(tert-butyl)phenyl)-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-(((benzyloxy)carbonyl)amino)-3-methylbutanoate 55 (120 mg, 0.166 mmol)in AcOH (1.5 mL) was added HBr (33% in AcOH, 1.5 mL). The mixture wasstirred for 1 h and then concentrated. The residue was dissolved in DMF(2 mL) and adjusted to pH=7 with TEA. After concentration, the residuewas purified by prep-HPLC to give(2R)-(3-(4-((2-(4-(tert-butyl)phenyl)-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-amino-3-methylbutanoate I-49 (12.8 mg) in 13% yield. MS (ESI) m/z:591.2 [M+H]⁺; ¹HNMR (DMSO-d₆, 400 MHz) δ 9.50 (t, J=6.0 Hz, 1H), 8.32(br s, 3H), 7.92 (d, J=8.0 Hz, 2H), 7.70-7.68 (m, 1H), 7.62-7.57 (m,4H), 5.86-5.72 (m, 2H), 5.35-5.32 (m, 1H), 4.65-4.39 (m, 4H), 3.96 (s,1H), 3.18-3.11 (m, 1H), 2.92-2.87 (m, 1H), 2.51-2.40 (m, 2H), 2.15-2.10(m, 2H), 1.31 (s, 9H), 0.94-0.92 (m, 6H).

Example 11 Compound I-52:N-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide

Compound I-52 was synthesized as shown in Scheme 11.

To a stirred solution of methyl 2-(bromomethyl)-4-cyanobenzoate 5 (2.04g, 8.05 mmol) and tert-butyl 4,5-diamino-5-oxopentanoate hydrochloride(1.95 g, 9.66 mmol) in DMF (20 mL) was added TEA (2.44 g, 24.14 mmol).The mixture was stirred at 40° C. overnight and then concentrated. Theresidue was dissolved in EA, washed with water, filtered, andconcentrates to give tert-butyl5-amino-4-(5-cyano-1-oxoisoindolin-2-yl)-5-oxopentanoate 60 (1.8 g) in65.3% yield. MS (ESI) m/z: 343.2 [M+H]⁺.

To a stirred solution of tert-butyl5-amino-4-(5-cyano-1-oxoisoindolin-2-yl)-5-oxopentanoate 60 (1.8 g, 5.25mmol) in AcOH (20 mL), pyridine (40 mL), and water (20 mL) was addedsodium hypophosphite (2.3 g, 26.2 mmol) and Raney Ni. The mixture wasstirred for 2 h and then filtered and concentrates. The residue wasdissolved in DCM and 1 N HCl was added. The organic layer was separatedand concentrated. The residue was triturated with tert-butyl methylether to give tert-butyl5-amino-4-(5-formyl-1-oxoisoindolin-2-yl)-5-oxopentanoate 61 (1.27 g) in70% yield. MS (ESI) m/z: 347.1 [M+H]⁺.

To a stirred solution of tert-butyl5-amino-4-(5-formyl-1-oxoisoindolin-2-yl)-5-oxopentanoate 61 (1.27 g,3.67 mmol) in MeOH (30 mL) was added sodium borohydride (84 mg, 2.2mmol) at 0° C. The mixture was stirred at 0° C. for 10 min and then RTfor 3 h. Water was added and the mixture was extracted with EA. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered, andconcentrates to give tert-butyl5-amino-4-(5-(hydroxymethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 62(960 mg) in 75% yield. MS (ESI) m/z: 349.1 [M+H]⁺.

To a stirred solution of tert-butyl5-amino-4-(5-(hydroxymethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 62(960 mg, 2.76 mmol), 4-dimethylaminopyridine (35 mg, 0.28 mmol), and TEA(558 mg, 5.52 mmol) in DCM (20 mL) was added tosyl chloride (1.05 g,5.52 mmol). The mixture was stirred for 3 h, and then concentrated andpurified using silica gel eluting with PE/EA (1:2) to give tert-butyl5-amino-4-(5-(chloromethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 63(640 mg) in 64% yield. MS (ESI) m/z: 367.1 [M+H]⁺.

To a stirred solution tert-butyl5-amino-4-(5-(chloromethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 63(640 mg, 1.75 mmol) in THF (15 mL) was added trimethylsilyl cyanide (525mg, 5.25 mmol) and tetrabutylammonium fluoride (5.25 mL) was then addeddropwise. The mixture was stirred at 35° C. for 3 h, and thenconcentrated and purified using silica gel eluting with PE/EA (1:2) togive tert-butyl5-amino-4-(5-(cyanomethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 64 (450mg) in 72% yield. MS (ESI) m/z: 358.2 [M+H]⁺.

To a stirred solution of tert-butyl5-amino-4-(5-(cyanomethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 64 (400mg, 1.12 mmol) in THF (20 mL) was added Raney Ni. The mixture wasstirred for 3 h under H₂, and then filtered and concentrates to givetert-butyl5-amino-4-(5-(2-aminoethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 65(400 mg, crude). MS (ESI) m/z: 362.2 [M+H]⁺.

To a stirred solution of tert-butyl5-amino-4-(5-(2-aminoethyl)-1-oxoisoindolin-2-yl)-5-oxopentanoate 65(400 mg, 1.12 mmol) in THF (20 mL) was added TEA (340 mg, 3.36 mmol) anda solution of 2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetylchloride 11 (1.55 mmol) in DCM (5 mL) at 0° C. The mixture was stirredat 0° C. for 10 min and RT for 3 h, and then concentrated. The residuewas purified by prep-TLC (EA) to give tert-butyl5-amino-5-oxo-4-(1-oxo-5-(2-(2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamido)ethyl)isoindolin-2-yl)pentanoate66 (400 mg) in 59% yield. MS (ESI) m/z: 602.2 [M+H]⁺.

To a stirred solution of tert-butyl5-amino-5-oxo-4-(1-oxo-5-(2-(2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamido)ethyl)isoindolin-2-yl)pentanoate66 (107 mg, 0.178 mmol) in DCM (3 mL) was added TFA (3 mL). The mixturewas stirred for 2 h and then concentrated to give5-amino-5-oxo-4-(1-oxo-5-(2-(2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)-phenyl)acetamido)ethyl)isoindolin-2-yl)pentanoicacid 67 (110 mg, crude). MS (ESI) m/z: 546.2 [M+H]⁺.

To a stirred solution5-amino-5-oxo-4-(1-oxo-5-(2-(2-oxo-2-(4-(1-(trifluoromethyl)-cyclopropyl)phenyl)acetamido)ethyl)isoindolin-2-yl)pentanoicacid 67 (0.178 mmol) in ACN (5 mL) was added CDI (145 mg, 0.89 mmol).The mixture was stirred at 95° C. overnight, and then concentrated andpurified by prep-TLC eluting with PE/EA (1:2) and then by prep-HPLC togive compound I-52 (27.8 mg) in 30% yield. MS (ESI) m/z: 528.1 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 9.01 (t, J=6.0 Hz, 1H),7.81-7.83 (m, 2H), 7.66 (d, J=8.0 Hz, 1H), 7.59-7.61 (m, 2H), 7.51 (s,1H), 7.40 (d, J=8.0 Hz, 1H), 5.10 (dd, J=4.8, 13.2 Hz, 1H), 4.28-4.44(m, 2H), 3.55-3.57 (m, 2H), 2.97 (t, J=6.8 Hz, 2H), 2.88-2.92 (m, 1H),2.57-2.62 (m, 1H), 2.38-2.42 (m, 1H), 1.98-2.01 (m, 1H), 1.39-1.42 (m,2H), 1.17-1.19 (m, 2H).

Example 12 Compound I-61:2-(4-(Tert-butyl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide

Compound I-61 was synthesized as shown in Scheme 12.

To a solution of 4-(tert-butyl)piperidine hydrochloride (150 mg, 0.85mmol) in DCM (6 mL) was added TEA (171 mg, 1.7 mmol) and methyl2-chloro-2-oxoacetate (124 mg, 1.02 mmol). The mixture was stirred for30 min and then concentrated. The residue was purified using silica geleluting with EA in PE from 30% to 50% to give methyl2-(4-(tert-butyl)piperidin-1-yl)-2-oxoacetate 70 (130 mg) in 68% yield.MS (ESI) m/z: 228.2 [M+H]⁺.

To a solution of methyl 2-(4-(tert-butyl)piperidin-1-yl)-2-oxoacetate 70(130 mg, 0.57 mmol) in THF/H₂O (4 mL/1 mL) was added LiOH (48 mg, 1.12mmol). The mixture was stirred at 25° C. for 16 h and then concentrated.The residue was adjusted to pH=5 using 1N HCl and then extracted withEA. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. The residue was purified using silica gel eluting withMeOH in DCM from 10% to 20% to give2-(4-(tert-butyl)piperidin-1-yl)-2-oxoacetic acid 71 (130 mg) in 99%yield. MS (ESI) m/z: 214.1 [M+H]⁺.

To a solution of methyl 2-(4-(tert-butyl)piperidin-1-yl)-2-oxoaceticacid 71 (52 mg, 0.24 mmol) in DCM (3 mL) was added oxalyl dichloride (46mg, 0.36 mmol) at 0° C., followed by addition of DMF (1 drop). Themixture was stirred at 25° C. for 1 h and then concentrated to give2-(4-(tert-butyl)piperidin-1-yl)-2-oxoacetyl chloride 72 (60 mg) in 98%yield.

To a solution of 2-(4-(tert-butyl)piperidin-1-yl)-2-oxoacetyl chloride72 (114 mg, 0.31 mmol) in DCM (4 mL) was added TEA (63 mg, 0.62 mmol)and 3-(4-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 25 (72mg, 0.31 mmol). The mixture was stirred for 1 h, and then concentratedand purified by prep-HPLC to give compound I-61 (49.9 mg) in 44% yield.MS (ESI) m/z: 469.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.00 (s, 1H),9.24 (d, J=4.0 Hz, 1H), 7.65 (s, 1H), 7.52 (d, J=4.4 Hz, 2H), 5.16 (dd,J=3.6, 12.4 Hz, 1H), 4.57-4.35 (m, 5H), 3.75 (t, J=12.8 Hz, 1H),2.98-2.90 (m, 2H), 2.65-2.56 (m, 2H), 2.42-2.34 (m, 1H), 2.04-2.01 (m,1H), 1.73-1.66 (m, 2H), 1.28-1.23 (m, 1H), 1.11-1.01 (m, 2H), 0.83 (s,9H).

Example 13 Compound I-63:N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)propanamide

Compound I-63 was synthesized as shown in Scheme 13.

To a stirred solution of1-bromo-4-(1-(trifluoromethyl)cyclopropyl)benzene 75 (2.3 g, 8.68 mmol)in THF (20 mL) was dropwise added n-butyllithium (2.5 M solution inhexane, 5.2 mL) at −78° C. under N₂. After stirring for 1 h at −78° C.,DMF (2 mL) was added and the mixture was stirred at −78° C. for 1 h. Themixture was quenched with saturated ammonium chloride and extracted withEA. The organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrates to give4-(1-(trifluoromethyl)cyclopropyl)benzaldehyde 76 (1.8 g) in 97% yield.¹H NMR (400 MHz, CDCl₃) δ 10.02 (s, 1H), 7.86 (d, J=8.0 Hz, 2H), 7.63(d, J=8.0 Hz, 2H), 1.41-1.43 (m, 2H), 1.06-1.08 (m, 2H).

To a stirred solution of 4-(1-(trifluoromethyl)cyclopropyl)benzaldehyde76 (500 mg, 2.34 mmol) in acetic anhydride (5 mL) was added2-acetamidoacetic acid (410 mg, 3.5 mmol) and sodium acetate trihydrate(287 mg, 3.5 mmol). The mixture was stirred at 120° C. overnight, andthen cooled to RT, poured into ice-water, and extracted with EA. Theorganic layer was washed with brine, dried over Na₂SO₄, concentrates,and purified using silica gel (PE/EA (4:1) to give(Z)-2-methyl-4-(4-(1-(trifluoromethyl)cyclopropyl)benzylidene)oxazol-5(4H)-one77 (180 mg, crude). MS (ESI) m/z: 296.1 [M+H]⁺; ¹H NMR (400 MHz, CDCl₃)δ 8.04 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 7.12 (s, 1H), 2.41 (s,3H), 1.41-1.43 (m, 2H), 1.06-1.08 (m, 2H).

A solution of(Z)-2-methyl-4-(4-(1-(trifluoromethyl)cyclopropyl)benzylidene)oxazol-5(4H)-one77 (180 mg, 0.61 mmol) in 4 N HCl (8 mL) was stirred at 100° C. for 2 hand then filtered and purified by prep-HPLC to give2-oxo-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)propanoic acid 78. MS(ESI) m/z: 271.1 [M−H]⁺.

To a stirred solution3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionehydrochloride 8 (47 mg, 0.15 mmol) and2-oxo-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-propanoic acid 78 (40mg, 0.15 mmol) in DMF (2 mL) was added DIEA (106 mg, 0.5 mmol),1-hydroxybenzotriazole (40 mg, 0.3 mmol), and EDAC.HCl (58 mg, 0.3mmol). The mixture was stirred for 2 h and then concentrated. Theresidue was purified by prep-HPLC to give compound I-63 (2.9 mg). MS(ESI) m/z: 527.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.76(t, J=6.0 Hz, 1H), 7.69-7.70 (m, 1H), 7.60-7.58 (m, 1H), 7.51-7.43 (m,5H), 6.73-6.69 (m, 1H), 5.10 (dd, J=5.2, 13.2 Hz, 1H), 4.52-4.29 (m,4H), 2.95-2.87 (m, 1H), 2.62-2.57 (m, 1H), 2.40-2.36 (m, 1H), 2.01-1.98(m, 1H), 1.35-1.33 (m, 2H), 1.14-1.12 (m, 2H).

Example 14 Compound I-70:N¹-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-N²,N²-dimethyloxalamide

Compound I-70 was synthesized as shown in Scheme 14.

To a solution of 2-(dimethylamino)-2-oxoacetic acid (30 mg, 0.26 mmol)in DMF (1.5 mL) was added3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione(80 mg, 0.26 mmol), HATU (148 mg, 0.39 mmol), and DIEA (105 mg, 0.78mmol). The mixture was stirred for 1 h and then concentrated. Theresidue was purified by prep-HPLC to give compound I-70 (32 mg) in 32%yield. MS (ESI) m/z: 379.2 [M+H]⁺.

The following compounds were prepared according to a synthetic proceduredescribed herein.

Compound I-6:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 460.1 [M+1]⁺.

Compound I-7:2-(4-dimethylaminophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 455.1 [M+1]⁺.

Compound I-8:2-phenyl-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 412.0 [M+1]⁺.

Compound I-9:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(thiophen-2-yl)-2-oxoacetamide.MS (ESI) m/z: 418.0 [M+1]⁺.

Compound I-10:(S)-2-(4-(tert-butyl)phenyl)-N-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 476.2 [M+1]⁺.

Compound I-11:2-(4-methoxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 442.0 [M+1]⁺.

Compound I-12:2-(4-cyclopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 452.1 [M+1]⁺.

Compound I-13:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 482.1 [M+H]⁺.

Compound I-14:2-(4-isopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 454.1 [M+1]⁺.

Compound I-15:2-(4-(sec-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 468.1 [M+1]⁺.

Compound I-16:2-(4-hydroxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 428.1 [M+1]⁺.

Compound I-17:2-(4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 426.5 [M+1]⁺.

Compound I-18:2-(4-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 446.0 [M+1]⁺.

Compound I-19:2-(3-tert-butylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 468.1 [M+1]⁺.

Compound I-20:2-(4-acetamidophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 469.1 [M+1]⁺.

Compound I-21:2-([1,1′-biphenyl]-4-yl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 488.1 [M+1]⁺.

Compound I-22:2-(4-fluorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 430.5 [M+1]⁺.

Compound I-23:2-(4-trifluoromethylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 480.0 [M+1]⁺.

Compound I-24:2-(3,4-dichlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 481.0 [M+1]⁺.

Compound I-25:2-(4-((dimethylamino)methyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 469.1 [M+1]⁺.

Compound I-26:2-(4-(morpholinomethyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 511.1 [M+1]⁺.

Compound I-27:2-(3-methyl-4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 482.1 [M+1]⁺.

Compound I-29:2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 480.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.03 (s, 1H),9.50 (t, J=6.0 Hz, 1H), 7.94 (d, J=7.6 Hz, 2H), 7.61 (d, J=8.4 Hz, 2H),7.48 (dd, J=2.4, 7.6 Hz, 1H), 7.41 (dd, J=2.4, 10.0 Hz, 1H), 5.16 (dd,J=5.2, 13.2 Hz, 1H), 4.59-4.41 (m, 4H), 2.98-2.88 (m, 1H), 2.67-2.60 (m,1H), 2.43-2.33 (m, 1H), 2.07-2.02 (m, 1H), 1.31 (s, 9H).

Compound I-30:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide.MS (ESI) m/z: 514.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.53 (t, J=5.2 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H), 7.67-7.52 (m, 5H), 5.16(dd, J=5.6, 13.2 Hz 1H), 4.60-4.42 (m, 4H), 2.96-2.89 (m, 1H), 2.66-2.58(m, 1H), 2.31-2.26 (m, 1H), 2.04-1.99 (m, 1H), 1.40 (s, 2H), 1.17 (s,2H).

Compound I-31:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)-2-oxoacetamide.MS (ESI) m/z: 509.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.60 (t, J=5.6 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H), 7.94 (s, 1H), 7.46 (d,J=8.4 Hz, 2H), 5.03 (dd, J=5.2, 13.2 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H),4.38-4.22 (m, 2H), 3.55-3.52 (m, 2H), 3.09-3.06 (m, 2H), 2.92-2.88 (m,2H), 2.86-2.82 (m, 3H), 2.61-2.50 (m, 1H), 2.05-2.02 (m, 1H), 1.99-1.98(m, 3H), 1.87-1.84 (m, 2H).

Compound I-33:2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 462.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.54 (t, J=6.0 Hz, 1H), 7.92 (t, J=1.6 Hz, 1H), 7.81-7.78 (m, 1H), 7.73(d, J=7.6 Hz, 1H), 7.58 (s, 1H), 7.54-7.49 (m, 2H), 5.12 (dd, J=5.2,13.6 Hz, 1H), 4.58 (d, J=6.0 Hz, 2H), 4.48-4.31 (m, 2H), 2.95-2.87 (m,1H), 2.67-2.58 (m, 1H), 2.42-2.33 (m, 1H), 2.03-1.98 (m, 1H), 1.27 (s,9H).

Compound I-34:2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-N-methyl-2-oxoacetamide.MS (ESI) m/z: 476.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),7.83-7.38 (m, 7H), 5.14-5.08 (m, 1H), 4.81-4.33 (m, 4H), 2.95-2.83 (m,4H), 2.62-2.58 (m, 1H), 2.49-2.40 (m, 1H), 2.02-1.99 (m, 1H), 1.31 (s,9H).

Compound I-35:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide.MS (ESI) m/z=468.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H),9.65 (t, J=5.6 Hz, 1H), 7.87 (s, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.62 (d,J=8.8 Hz, 2H), 7.19 (s, 1H), 4.99 (dd, J=5.2, 13.6 Hz, 1H), 4.69 (d,J=7.0 Hz, 2H), 4.39-4.21 (m, 2H), 2.92-2.84 (m, 1H), 2.60-2.56 (m, 1H),2.37-2.32 (m, 1H), 2.02-1.97 (m, 1H), 1.31 (s, 9H).

Compound I-36:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-2-(4-(1,1,1-trifluoropropan-2-yl)phenyl)acetamide.MS (ESI) m/z: 508.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.62 (t, J=6.4 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.93 (s, 1H), 7.62 (d,J=8.0 Hz, 2H), 5.03 (dd, J=4.8, 13.2 Hz, 1H), 4.60 (d, J=6.0 Hz, 2H),4.37-4.22 (m, 2H), 4.02-3.93 (m, 1H), 2.93-2.84 (m, 1H), 2.61-2.51 (m,1H), 2.35-2.25 (m, 1H), 2.01-1.98 (m, 1H), 1.48 (d, J=7.2 Hz, 2H).

Compound I-37:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide.MS (ESI) m/z: 454.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H),9.56 (t, J=6.4 Hz, 1H), 8.08 (d, J=4.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H),7.53 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.11 (d, J=4.0 Hz, 1H), 5.11 (dd,J=5.2, 13.6 Hz, 1H), 4.52 (d, J=6.4 Hz, 2H), 4.48-4.30 (m, 2H),3.28-3.23 (m, 1H), 2.92-2.86 (m, 1H), 2.62-2.57 (m, 1H), 2.40-2.33 (m,1H), 2.02-1.98 (m, 1H), 1.32 (d, J=6.8 Hz, 6H).

Compound I-39:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)-2-oxoacetamide.MS (ESI) m/z=468.0 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H),9.41 (t, J=6.0 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.85 (s, 1H), 7.60 (d,J=8.4 Hz, 2H), 5.02 (dd, J=5.2, 13.2 Hz, 1H), 4.48 (d, J=6.0 Hz, 2H),4.43-4.28 (m, 2H), 2.93-2.86 (m, 1H), 2.67-2.60 (m, 1H), 2.33-2.30 (m,1H), 2.05-2.00 (m, 1H), 1.31 (s, 9H).

Compound I-40:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 482.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),8.02 (s, 1H), 7.81-7.78 (m, 2H), 7.65-7.58 (m, 2H), 5.04 (dd, J=5.2,13.2 Hz, 1H), 4.89-4.61 (m, 2H), 4.41-4.15 (m, 2H), 3.03-2.88 (m, 4H),2.61-2.57 (m, 1H), 2.34-2.27 (m, 1H), 2.03-1.98 (m, 1H), 1.30 (s, 9H).

Compound I-41:2-(4-(tert-butyl)phenyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)-2-oxoacetamide.MS (ESI) m/z=482.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H),9.03 (t, J=5.6 Hz, 1H), 7.88 (s, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.54 (d,J=8.4 Hz, 2H), 4.99 (dd, J=5.2, 13.2 Hz, 1H), 4.30 (d, J=15.6 Hz, 1H),4.16 (d, J=15.2 Hz, 1H), 3.53-3.55 (m, 2H), 3.05 (t, J=6.8 Hz, 2H),2.90-2.80 (m, 1H), 2.57-2.54 (m, 1H), 2.28-2.17 (m, 1H), 1.82-1.79 (m,1H), 1.30 (s, 9H).

Compound I-42:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-methylcyclopropyl)phenyl)-2-oxoacetamide.MS (ESI) m/z: 466.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.56 (t, J=5.6 Hz, 1H), 7.93 (s, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.37 (d,J=8.4 Hz, 2H), 5.02 (dd, J=4.8, 13.2 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H),4.36-4.21 (m, 2H), 2.88-2.85 (m, 1H), 2.60-2.56 (m, 1H), 2.31-2.27 (m,1H), 2.00-1.97 (m, 1H), 1.42 (s, 3H), 0.96-0.94 (m, 2H), 0.90-0.87 (m,2H).

Compound I-43:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)-2-oxoacetamide.MS (ESI) m/z: 484.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H),9.61 (t, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.94 (d, J=11.2 Hz, 2H), 7.60 (d,J=11.6 Hz, 2H), 5.07 (dd, J=6.8, 10.0 Hz, 1H), 4.79 (t, J=7.2 Hz, 1H),4.63 (d, J=7.6 Hz, 2H), 4.42-4.24 (m, 2H), 3.49 (d, J=7.2 Hz, 2H),2.98-2.86 (m, 1H), 2.76-2.64 (m, 1H), 2.46-2.27 (m, 1H), 2.04-1.97 (m,1H), 1.28 (s, 6H).

Compound I-44:2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 469.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.55 (t, J=6.4 Hz, 1H), 7.94 (s, 1H), 7.56-7.54 (m, 2H), 7.34 (d, J=7.6Hz, 1H), 5.02 (dd, J=5.2, 13.2 Hz, 1H), 4.59 (d, J=6.0 Hz, 2H),4.37-4.22 (m, 2H), 2.93-2.84 (m, 1H), 2.63 (s, 6H), 2.61-2.54 (m, 1H),2.34 (s, 3H), 2.31-2.27 (m, 1H), 2.03-1.97 (m, 1H).

Compound I-45:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamide.MS (ESI) m/z=468.1 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H),9.62 (t, J=5.6 Hz, 1H), 7.93 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.0 Hz, 2H),7.14 (s, 1H), 4.99 (dd, J=5.2, 13.2 Hz, 1H), 4.64 (d, J=4.8 Hz, 2H),4.53-4.36 (m, 2H), 2.88-2.84 (m, 1H), 2.67-2.58 (m, 1H), 2.39-2.30 (m,1H), 2.00-1.97 (m, 1H), 1.31 (s, 9H).

Compound I-46:2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 462.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.05 (s, 1H),9.55 (t, J=7.2 Hz, 1H), 7.94 (t, J=10.4 Hz, 1H), 7.82 (dd, J=2.0, 10.4Hz, 2H), 7.71 (d, J=9.6 Hz, 1H), 7.64-7.52 (m, 3H), 5.20 (dd, J=6.4,18.0 Hz, 1H), 4.65-4.44 (m, 4H), 3.00-2.90 (m, 1H), 2.75-2.61 (m, 1H),2.44-2.37 (m, 1H), 2.07-2.01 (m, 1H), 1.30 (s, 9H).

Compound I-48:2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 476.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.15 (s, 1H),9.52 (t, J=5.6 Hz, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.92-7.85 (m, 2H), 7.78(d, J=8.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 5.17 (dd, J=5.2, 12.8 Hz,1H), 4.91 (dd, J=2.0, 5.6 Hz, 1H), 2.92-2.86 (m, 1H), 2.60-2.56 (m, 1H),2.54-2.53 (m, 1H), 2.06-2.05 (m, 1H), 1.31 (s, 9H).

Compound I-50:2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 480.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.44 (t, J=6.0 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.74 (dd, J=4.8, 8.4 Hz,1H), 7.59 (d, J=8.4 Hz, 2H), 7.41 (dd, J=8.8, 10.0 Hz, 1H), 5.14 (dd,J=4.8, 12.8 Hz, 1H), 4.66-4.49 (m, 4H), 2.95-2.87 (m, 1H), 2.63-2.59 (m,1H), 2.38-2.33 (m, 1H), 2.02-1.97 (m, 1H), 1.30 (s, 9H).

Compound I-51:2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 498.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.04 (s, 1H),9.51 (t, J=5.6 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.78 (t, J=7.8 Hz, 1H),7.60 (d, J=8.4 Hz, 2H), 5.15 (dd, J=5.2, 13.2 Hz, 1H), 4.66-4.47 (m,4H), 2.98-2.87 (m, 1H), 2.66-2.59 (m, 1H), 2.36 (qd, J=4.4, 13.2 Hz,1H), 2.08-1.96 (m, 1H), 1.30 (s, 9H).

Compound I-53:2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 454.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.58 (t, J=6.4 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.89 (dd, J=1.6, 8.0 Hz,1H), 7.72 (d, J=7.6 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 7.48(d, J=8.4 Hz, 1H), 5.11 (dd, J=5.2, 13.2 Hz, 1H), 4.57 (d, J=6.0 Hz,2H), 4.49-4.31 (m, 2H), 2.96-2.67 (m, 1H), 2.62-2.57 (m, 1H), 2.43 (s,1H), 2.02-1.98 (m, 1H).

Compound I-54:2-(3-methyl-4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 476.0 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.01 (s, 1H),9.47 (t, J=5.6 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.68 (d, J=4.4 Hz, 2H),7.60-7.51 (m, 3H), 5.18 (dd, J=4.8, 12.8 Hz, 1H), 4.63-4.45 (m, 4H),2.97-2.89 (m, 1H), 2.64-2.60 (m, 1H), 2.54 (s, 3H), 2.46-2.33 (m, 1H),2.07-1.90 (m, 1H), 1.38 (s, 9H).

Compound I-55:2-(3-methyl-4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 476.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H),9.50 (t, J=5.6 Hz, 1H), 7.76-7.70 (m, 3H), 7.56-7.48 (m, 3H), 5.11 (dd,J=5.2, 13.2 Hz, 1H), 4.56 (d, J=6.0 Hz, 2H), 4.49-4.31 (m, 2H),2.92-2.87 (m, 1H), 2.67-2.62 (m, 1H), 2.56 (s, 3H), 2.34-2.32 (m, 1H),2.03-1.90 (m, 1H), 1.39 (s, 9H).

Compound I-56:2-(4-(tert-butyl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-oxoacetamide.MS (ESI) m/z: 448.5 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 10.95 (s, 1H),8.20-9.51 (m, 7H), 5.16 (dd, 1H), 4.48 (q, 2H), 2.91 (m, 1H), 2.60 (m,1H), 2.42 (m, 1H), 2.04 (m, 1H), 1.32 (s, 9H).

Compound I-57:N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide.MS (ESI) m/z: 500.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.00 (d, 1H),7.64-8.10 (m, 7H), 5.14 (dd, 1H), 4.49 (q, 2H), 2.92 (m, 1H), 2.58 (m,1H), 2.40 (m, 1H), 2.04 (m, 1H), 1.43 (m, 2H), 1.22 (m, 2H).

Compound I-58:N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide.MS (ESI) m/z: 527.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.14 (s, 1H),9.55-9.58 (t, 1H), 8.03-8.07 (d, 2H), 7.85-7.90 (m, 3H), 7.78-7.81 (d,2H), 5.16-5.19 (m, 1H), 4.88-4.97 (m, 2H), 2.87-2.95 (m, 1H), 2.51-2.64(m, 2H), 2.04-2.09 (m, 1H), 1.81-1.45 (m, 2H), 1.16-1.25 (m, 3H).

Compound I-59:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamide.MS (ESI) m/z: 453.9 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.01 (s, 1H),9.54 (t, J=5.6 Hz, 1H), 8.05 (d, J=3.6 Hz, 1H), 7.66 (d, J=6.8 Hz, 1H),7.57-7.49 (m, 2H), 7.10 (d, J=3.6 Hz, 1H), 5.15 (dd, J=4.4, 12.8 Hz,1H), 4.58-4.41 (m, 4H), 3.28-3.22 (m, 1H), 2.96-2.88 (m, 1H), 2.64-2.60(m, 1H), 2.40-2.36 (m, 1H), 2.05-2.02 (m, 1H), 1.31 (d, J=6.4 Hz, 6H).

Compound I-60:N-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide.MS (ESI) m/z: 527.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.47 (t, J=5.6 Hz, 1H), 7.99 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H),7.58 (d, J=7.6 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 5.13 (dd, J=5.2, 13.2Hz, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.48-4.26 (m, 2H), 2.98-2.90 (m, 1H),2.63-2.59 (m, 1H), 2.47-2.40 (m, 1H), 2.33 (s, 3H), 2.02-1.99 (m, 1H),1.41 (t, J=4.8 Hz, 2H), 1.22 (t, J=4.8 Hz, 2H).

Compound I-62:2-(4-(tert-butyl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 469.2[M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s, 1H),9.28 (t, J=6.0 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.49 (s, 1H), 7.42 (d,J=8.0 Hz, 1H), 5.10 (dd, J=4.8, 13.2 Hz, 1H), 4.29-4.35 (m, 4H),4.35-3.77 (m, 1H), 3.79 (d, J=11.6 Hz, 1H), 3.00-2.86 (m, 2H), 2.62-2.56(m, 2H), 2.49-2.37 (m, 1H), 2.01-1.98 (m, 1H), 1.74-1.65 (m, 2H),1.30-1.23 (m, 1H), 1.16-1.04 (m, 2H), 0.84 (s, 9H).

Compound I-63:N-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide.MS (ESI) m/z: 527.9 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H),8.76 (t, J=6.0 Hz, 1H), 7.69-7.70 (m, 1H), 7.60-7.58 (m, 1H), 7.51-7.43(m, 5H), 6.73-6.69 (m, 1H), 5.10 (dd, J=5.2, 13.2 Hz, 1H), 4.52-4.29 (m,4H), 2.95-2.87 (m, 1H), 2.62-2.57 (m, 1H), 2.40-2.36 (m, 1H), 2.01-1.98(m, 1H), 1.35-1.33 (m, 2H), 1.14-1.12 (m, 2H).

Compound I-64:(2,6-dioxo-3-(1-oxo-4-((2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)-phenyl)acetamido)methyl)isoindolin-2-yl)piperidin-1-yl)methylD-valinate. MS (ESI) m/z: 643.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 9.58(t, J=6.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 2H), 7.68-7.56 (m, 5H), 5.73-5.62(m, 2H), 5.36-5.32 (m, 1H), 4.65-4.39 (m, 4H), 3.32 (s, 1H), 3.22-3.08(m, 1H), 2.88-2.84 (m, 1H), 2.51-2.42 (m, 1H), 2.10-2.07 (m, 1H),1.85-1.83 (m, 1H), 1.43-1.40 (m, 2H), 1.24-1.20 (m, 2H), 0.86-0.78 (m,6H).

Compound I-65:N-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide.MS (ESI) m/z: 528.1 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 10.98 (s, 1H),9.03 (t, J=5.6 Hz, 1H), 7.79 (d, J=5.2 Hz, 2H), 7.65-7.58 (m, 3H),7.54-7.48 (m, 2H), 5.12 (dd, J=5.2, 13.2 Hz, 1H), 4.53-4.33 (m, 2H),3.61-3.59 (m, 2H), 2.93-2.87 (m, 3H), 2.61-2.51 (m, 1H), 2.40-2.29 (m,1H), 1.91-1.87 (m, 1H), 1.42-1.39 (m, 2H), 1.19 (s, 2H).

Compound I-66:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(piperidin-4-yl)phenyl)acetamide.MS (ESI) m/z: 489.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 10.98 (s, 1H),9.56 (d, J=6.0 Hz, 1H), 8.80 (d, J=63.2 Hz, 2H), 7.98 (d, J=8.4 Hz, 2H),7.73 (d, J=7.6 Hz, 1H), 7.56 (s, 1H), 7.50-7.44 (m, 3H), 5.12 (dd,J=5.2, 13.2 Hz, 1H), 4.57-4.31 (m, 2H), 3.04-2.92 (m, 5H), 2.73 (d,J=4.4 Hz, 3H), 2.63-2.58 (m, 1H), 2.45-2.38 (m, 1H), 2.03-1.85 (m, 5H).

Compound I-67:2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 468.2 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.01 (s, 1H),9.22 (t, J=6.0 Hz, 1H), 7.62-7.65 (m, 1H), 7.50-7.49 (m, 2H), 5.14 (dd,J=5.2, 13.2 Hz, 1H), 4.55-4.37 (m, 4H), 3.10-3.08 (m, 1H), 2.93-2.89 (m,1H), 2.65-2.60 (m, 1H), 2.38-2.35 (m, 1H), 2.07-2.01 (m, 1H), 1.90-1.87(m, 2H), 1.80-1.78 (m, 2H), 1.16-0.94 (m, 5H), 0.83 (s, 9H).

Compound I-68:2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 468.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H),9.23 (t, J=6.4 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.47 (s, 1H), 7.40 (d,J=8.0 Hz, 1H), 5.10 (dd, J=5.2, 13.2 Hz, 1H), 4.46-4.28 (m, 4H),3.14-3.07 (m, 1H), 2.95-2.86 (m, 1H), 2.62-2.57 (m, 1H), 2.44-2.32 (m,1H), 2.02-1.97 (m, 1H), 1.91-1.89 (m, 2H), 1.81-1.78 (m, 2H), 1.21-0.92(m, 5H), 0.83 (s, 9H).

Compound I-69:N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxo-4-phenylbutanamide.MS (ESI) m/z=440.1 [M+H]⁺.

Compound I-71:N¹-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-N²,N²-dimethyloxalamide.MS (ESI) m/z=379.1 [M+H]⁺.

Compound I-72:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(p-tolyl)acetamide.MS (ESI) m/z: 420.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.48 (t, 1H), 7.38-7.89 (m, 7H), 5.17 (dd, 1H), 4.42-4.59 (m, 4H), 2.93(m, 1H), 2.60 (m, 1H), 2.36 (m, 4H), 2.02 (m, 1H).

Compound I-73:2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 442.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.59 (t, 1H), 7.52-8.08 (m, 6H), 5.15 (dd, 1H), 4.42-4.59 (m, 4H), 2.93(m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-74:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-phenylacetamide.MS (ESI) m/z: 405.3 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.52-9.56 (t, 1H), 7.95-8.0 (m, 2H), 7.68-7.99 (d, 2H), 7.53-7.60 (m,4H), 5.14-5.18 (d, 2H), 4.55-4.60 (m, 3H), 4.43-4.47 (d, 1H), 3.55-3.62(m, 1H), 3.10-3.15 (m, 1H), 2.92-2.98 (m, 1H).

Compound I-75:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(trifluoromethyl)phenyl)acetamide.MS (ESI) m/z: 474.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.03 (s, 1H),9.61 (t, 1H), 7.54-8.21 (m, 7H), 5.17 (dd, 1H), 4.44-4.60 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-76:2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 431.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.04 (s, 1H),9.60 (t, 1H), 7.52-8.17 (m, 7H), 5.17 (dd, 1H), 4.43-4.60 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-77:2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 440.8 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.03 (s, 1H),9.55 (t, 1H), 7.65-8.01 (m, 7H), 5.17 (dd, 1H), 4.46-4.56 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-78:2-(4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 436.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.03 (s, 1H),9.45 (t, 1H), 7.09-7.99 (m, 7H), 5.17 (dd, 1H), 4.42-4.60 (m, 4H), 3.87(s, 3H), 2.92 (m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-79:2-(2,4,6-trimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 496.5 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.54 (t, 1H), 7.25-7.67 (m, 5H), 5.15 (dd, 1H), 4.44-4.61 (m, 4H), 3.77(m, 9H), 2.92 (m, 1H), 2.61 (m, 1H), 2.38 (m, 1H), 2.03 (m, 1H).

Compound I-80:2-(2,4,6-trimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 448.5 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.56 (t, 1H), 7.51-7.67 (m, 3H), 6.90 (s, 2H), 5.15 (dd, 1H), 4.39-4.57(m, 4H), 2.93 (m, 1H), 2.61 (m, 1H), 2.36 (m, 1H), 2.25 (s, 3H), 2.08(s, 6H), 2.03 (m, 1H).

Compound I-81:2-(4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 423.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.03 (s, 1H),9.52-9.55 (t, 1H), 8.08-8.11 (m, 2H), 7.65-7.68 (m, 1H), 7.53-7.60 (m,2H), 7.40-7.44 (t, 2H), 5.14-5.18 (m, 1H), 4.53-4.60 (m, 3H), 4.43-4.49(d, 1H), 2.90-2.96 (m, 1H), 2.61-2.67 (m, 1H), 2.37-2.44 (m, 1H),1.91-2.02 (m, 1H).

Compound I-82:2-(2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 423.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.49 (t, 1H), 7.83-7.89 (m, 1H), 7.77-7.82 (m, 1H), 7.67-7.70 (m, 1H),7.53-7.60 (m, 2H), 7.35-7.41 (m, 2H), 5.13-5.17 (m, 1H), 4.52-4.59 (m,3H), 4.42-4.48 (d, 1H), 2.90-2.96 (m, 1H), 2.60-2.65 (m, 1H), 2.34-2.40(m, 1H), 2.00-2.05 (m, 1H).

Compound I-83:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-phenylacetamide.MS (ESI) m/z: 405.8 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 10.99 (s, 1H),9.57 (t, 1H), 7.99-8.02 (m, 2H), 7.76-7.84 (m, 2H), 7.57-7.61 (m, 3H),7.48-7.50 (m, 1H), 5.10-5.14 (m, 1H), 4.58-4.61 (m, 2H), 4.46-4.49 (m,1H), 4.35-4.37 (m, 1H), 2.87-2.95 (m, 1H), 2.59-2.63 (m, 1H), 2.35-2.44(m, 1H), 1.99-2.05 (m, 1H).

Compound I-84:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6-trimethoxyphenyl)acetamide.MS (ESI) m/z: 496.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H),9.56 (s, 1H), 7.74 (d, 1H), 7.72 (s, 1H), 7.58 (d, 1H), 7.27 (s, 2H),5.12 (dd, 1H), 4.58 (d, 2H), 4.34-4.44 (d, 1H), 4.34-4.30 (d, 1H), 3.78(s, 9H), 2.53-2.88 (m, 1H), 2.62-2.59 (d, 1H), 2.44-2.36 (m, 1H), 2.31(s, 3H), 2.02-1.99 (m, 1H).

Compound I-85:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6-trimethylphenyl)acetamide.MS (ESI) m/z: 448.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.57 (s, 1H), 7.70 (d, 1H), 7.51 (s, 1H), 7.46 (d, 1H), 6.90 (s, 2H),5.13-5.09 (dd, 1H), 4.50 (d, 2H), 4.44 (d, 1H), 4.33 (d, 1H), 2.95-2.98(m, 1H), 2.62 (d, 1H), 2.44-2.37 (mm, 1H), 2.26 (s, 3H), 2.11 (s, 6H),2.02-1.99 (m, 1H).

Compound I-86:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2-fluorophenyl)acetamide.MS (ESI) m/z: 424.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H),9.52 (s, 1H), 7.86 (m, 1H), 7.83 (m, 1H), 7.72 (s, 1H), 7.55 (m, 1H),7.47-7.40 (m, 1H), 7.29 (m, 2H), 5.18-5.10 (m, 1H), 4.56 (d, 2H), 4.45(d, 1H), 4.31 (d, 1H), 2.95-288 (m, 1H), 2.62-2.51 (d, 1H), 2.44-2.38(m, 1H), 2.03-1.99 (m, 1H).

Compound I-87:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-trifluoromethylphenyl)acetamide.MS (ESI) m/z: 474.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.65 (t, 1H), 7.57-8.23 (m, 7H), 5.12 (dd, 1H), 4.35-4.60 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-88:2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 440.8 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 10.98 (s, 1H),9.65 (t, 1H), 7.57-8.23 (m, 7H), 5.11 (dd, 1H), 4.35-4.60 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-89:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-methoxyphenyl)-2-oxoacetamide.MS (ESI) m/z: 435.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H),9.49 (t, 1H), 7.99-8.01 (m, 2H), 7.72-7.76 (m, 1H), 7.52 (s, 1H),7.44-7.49 (m, 1H), 7.10-7.14 (m, 2H), 5.08-5.15 (m, 1H), 4.52-4.56 (m,2H), 4.45-4.49 (m, 1H), 4.31-4.35 (m, 1H), 3.87 (s, 3H), 2.90-2.97 (m,1H), 2.55-2.64 (m, 1H), 2.36-2.45 (m, 1H), 1.99-2.06 (m, 1H).

Compound I-90:2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 431.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.64 (t, 1H), 7.57-8.18 (m, 7H), 5.10 (dd, 1H), 4.35-4.59 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-91:2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 440.8 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.62 (t, 1H), 7.50-8.15 (m, 7H), 5.11 (dd, 1H), 4.31-4.58 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Compound I-92:2-(3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 423.7 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.57 (t, 1H), 7.82-7.86 (m, 1H), 7.74-7.78 (m, 1H), 7.59-7.68 (m, 4H),7.53-7.56 (m, 1H), 5.14-5.18 (m, 1H), 4.54-4.60 (m, 2H), 4.43-4.47 (m,1H), 3.15-3.18 (d, 1H), 2.90-2.97 (m, 1H), 2.61-2.65 (m, 1H), 2.35-2.41(m, 1H), 2.02-2.05 (m, 1H).

Compound I-93:2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 441.7 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.62 (t, 1H), 8.10-8.15 (m, 1H), 7.92-7.98 (m, 1H), 7.67-7.73 (m, 2H),7.55 (s, 1H), 7.46-7.49 (d, 1H), 5.10-5.14 (m, 1H), 4.56-4.59 (m, 2H),4.44-4.48 (m, 1H), 4.31-4.34 (m, 1H), 2.83-2.87 (m, 1H), 2.49-2.52 (m,1H), 2.41-2.45 (m, 1H), 1.98-2.02 (m, 1H).

Compound I-94:2-(3-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 435.8 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.52 (t, 1H), 7.66-7.68 (m, 1H), 7.50-7.60 (m, 4H), 7.45-7.49 (m, 1H),7.30-7.33 (m, 1H), 5.14-5.18 (m, 1H), 4.54-4.60 (m, 2H), 4.43-4.46 (m,1H), 3.80 (s, 3H), 2.86-2.97 (m, 2H), 2.57-2.65 (m, 1H), 2.34-2.40 (m,1H), 1.99-2.04 (m, 1H).

Compound I-95:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-methoxyphenyl)-2-oxoacetamide.MS (ESI) m/z: 435.8 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.56 (t, 1H), 7.72-7.76 (d, 1H), 7.51-7.59 (m, 2H), 7.46-7.50 (m, 3H),7.28-7.32 (m, 1H), 5.10-5.13 (m, 1H), 4.56-4.59 (m, 2H), 4.41-4.46 (m,1H), 4.35-4.39 (m, 1H), 3.80 (s, 3H), 2.88-2.94 (m, 1H), 2.52-2.59 (m,1H), 2.36-2.44 (m, 1H), 2.00-2.03 (m, 1H).

Compound I-96:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-(naphthalen-2-yl)-2-oxoacetamide.MS (ESI) m/z: 456.5 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.59 (t, 1H), 7.56-8.15 (m, 10H), 5.16 (dd, 1H), 4.47-4.63 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.02 (m, 1H).

Compound I-97:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(naphthalen-2-yl)-2-oxoacetamide.MS (ESI) m/z: 456.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H),9.63 (t, 1H), 7.53-8.69 (m, 10H), 5.16 (dd, 1H), 4.33-4.64 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.02 (m, 1H).

Compound I-98:2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 434.4 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.50 (t, 1H), 7.37-7.69 (m, 6H), 5.15 (dd, 1H), 4.30-4.60 (m, 4H), 2.93(m, 1H), 2.61 (m, 1H), 2.41 (m, 1H), 2.38 (s, 6H), 2.03 (m, 1H).

Compound I-99:2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 434.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (s, 1H),9.52 (t, 1H), 7.37-7.75 (m, 6H), 5.13 (dd, 1H), 4.32-4.58 (m, 4H), 2.93(m, 1H), 2.61 (m, 1H), 2.41 (m, 1H), 2.38 (s, 6H), 2.03 (m, 1H).

Compound I-100:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-fluorophenyl)-2-oxoacetamide.MS (ESI) m/z: 423.8 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.61 (t, 1H), 7.88-7.95 (d, 1H), 7.73-7.80 (m, 1H), 7.65-7.70 (d, 1H),7.57-7.63 (m, 2H), 7.57 (s, 1H), 7.50-7.55 (m, 1H), 5.08-5.13 (m, 1H),4.56-4.59 (d, 2H), 4.45-4.50 (m, 1H), 4.31-4.37 (m, 1H), 2.88-2.96 (m,1H), 2.58-2.64 (m, 1H), 2.36-2.45 (m, 1H), 1.99-2.06 (m, 1H).

Compound I-101:2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 473.6 [M+H]⁺; ¹H NMR (DMSO-d₆, 400 MHz) δ 11.02 (s, 1H),9.60 (t, 1H), 8.22-8.25 (m, 1H), 7.96-8.01 (m, 1H), 7.85-7.89 (d, 1H),7.64-7.68 (m, 1H), 7.55-7.60 (m, 1H), 7.51-7.54 (m, 1H), 5.14-5.19 (m,1H), 4.55-4.60 (d, 1H), 4.51-4.55 (m, 2H), 4.43-4.47 (m, 1H), 2.89-2.96(m, 1H), 2.58-2.65 (m, 1H), 2.35-2.43 (m, 1H), 1.99-2.05 (m, 1H).

Compound I-102:2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 473.8 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),9.63 (t, 1H), 8.23 (s, 1H), 8.00-8.05 (m, 1H), 7.88-7.95 (d, 1H),7.70-7.75 (d, 1H), 7.57 (s, 1H), 7.46-7.50 (m, 1H), 5.09-5.15 (m, 1H),4.56-4.60 (d, 2H), 4.43-4.45 (m, 1H), 4.31-4.36 (m, 1H), 2.90-2.95 (m,1H), 2.56-2.62 (m, 1H), 2.38-2.44 (m, 1H), 1.99-2.04 (m, 1H).

Compound I-103:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(pyridin-4-yl)acetamide.MS (ESI) m/z: 407.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H),9.43 (s, 1H), 8.74 (s, 2H), 7.81 (d, 2H), 7.70 (d, 1H), 7.55 (s, 1H),7.46 (d, 1H), 5.12-5.08 (dd, 1H), 4.60 (d, 2H), 4.61-4.42 (d, 1H),4.32-4.29 (d, 1H), 2.90-2.87 (m, 1H), 2.62-2.59 (bd, 1H), 2.39-2.36 (m,1H), 2.01-1.99 (m, 1H).

Compound I-104:2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 490.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.86 (s, 1H),10.98 (s, 1H), 9.60 (s, 1H), 7.71 (d, 1H), 7.51 (s, 1H), 7.44 (m, 1H),7.09 (s, 2H), 5.12-5.09 (dd, 1H), 4.48 (d, 2H), 4.47-4.44 (d, 1H),4.33-4.29 (d, 1H), 2.95-2.87 (m, 1H), 2.61 (bd, 1H), 2.41-2.35 (m, 1H),2.13 (s, 6H), 2.01-1.99 (m, 1H), 1.26 (s, 9H).

Compound I-105:2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 490.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.01 (s, 1H),9.58 (s, 1H), 7.65 (s, 1H), 7.54 (m, 2H), 7.09 (s, 2H), 5.17-5.13 (dd,1H), 4.57-4.53 (d, 1H), 4.51 (d, 2H), 4.43-4.39 (d, 1H), 2.96-2.89 (m,1H), 2.50 (bd, 1H), 2.37-2.33 (m, 1H), 2.11 (s, 6H), 2.04-1.99 (m, 1H),1.26 (s, 9H).

Compound I-106:2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamide.MS (ESI) m/z: 485.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.02 (s, 1H),9.54 (s, 1H), 7.95 (d, 2H), 7.68 (d, 1H), 7.55 (d, 1H), 7.52 (d, 1H),5.18-5.14 (dd, 1H), 4.60 (d, 2H), 4.56-4.54 (m, 2H), 4.46 (d, 1H),2.97-2.89 (m, 1H), 2.64-2.51 (bd, 1H), 2.49-2.36 (m, 1H), 2.04-1.91 (m,1H).

Example 15 Compound II-1:1-(3-(Dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea

Compound II-1 was synthesized as shown in Scheme 15.

To a solution of triphosgene (119 mg, 0.40 mmol) in DCM (5 mL) was addeddropwise a solution of N¹,N¹,6-trimethylbenzene-1,3-diamine (150 mg, 1.0mmol) in DCM (5 mL) and TEA (200 mg, 2.0 mmol) at 0° C. for 30 min. Themixture was concentrated to give 5-isocyanato-N,N,2-trimethylaniline 80(176 mg), which was used directly in the next step without furtherpurification.

To a solution of3-(2-(aminomethyl)-6-oxo-4H-thieno[2,3-c]pyrrol-5(6H)-yl)piperidine-2,6-dioneTFA 81 (51.5 mg, 0.185 mmol) in THF (6 mL) at RT was added5-isocyanato-N,N,2-trimethylaniline 80 (32.5 mg, 0.185 mmol), followedby addition of TEA (37.4 mg, 0.371 mmol). After stirred at RT for 2 h,the mixture was concentrated and purified using silica gel eluting withMeOH/DCM from 0% to 6% to give compound II-1 (40.4 mg) in 48% yield. MS(ESI) m/z: 455.8 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H), 8.57(s, 1H), 7.14-7.11 (m, 2H), 6.96-6.95 (m, 2H), 6.73 (t, J=6.0 Hz, 1H),4.98 (dd, J=8.0, 13.2 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.36-4.18 (m,2H), 2.92-2.84 (m, 1H), 2.58-2.56 (m, 7H), 2.41-2.28 (m, 1H), 2.16 (s,3H), 1.99-1.97 (m, 1H).

Example 16 Compound II-149:(E)-N-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acrylamide

Compound II-149 was synthesized as shown in Scheme 16.

To a stirred solution of(Z)-2-methyl-4-(4-(1-(trifluoromethyl)cyclopropyl)-benzylidene)oxazol-5(4H)-one85 (0.6 mmol) in 1,4-dioxane (4 mL) was added 4 N HCl (4 mL). Themixture was stirred at 100° C. for 4 h, and then concentrated andpurified by prep-TLC eluting with DCM/MeOH (10:1) to give(E)-3-(4-(1-(trifluoromethyl)cyclopropyl)-phenyl)acrylic acid 86 (40mg). MS (ESI) m/z: 255.1 [M−H]⁺.

To a stirred solution3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 8 (60 mg,0.156 mmol) and (E)-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acrylicacid 86 (40 mg, 0.156 mmol) in DMF (2 mL) was added DIEA (60 mg, 0.45mmol), HOBt (43 mg, 0.32 mmol), and EDAC.HCl (62 mg, 0.32 mmol). Themixture was stirred for 2 h, and then concentrated and purified byprep-HPLC to give compound II-149 (8.1 mg). MS (ESI) m/z: 511.9 [M+H]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.76 (t, J=6.0 Hz, 1H),7.69-7.70 (m, 1H), 7.60-7.58 (m, 1H), 7.51-7.43 (m, 5H), 6.73-6.69 (m,1H), 5.10 (dd, J=5.2, 13.2 Hz, 1H), 4.52-4.29 (m, 4H), 2.95-2.87 (m,1H), 2.62-2.57 (m, 1H), 2.40-2.36 (m, 1H), 2.01-1.98 (m, 1H), 1.35-1.33(m, 2H), 1.14-1.12 (m, 2H).

Example 17 Compound II-165:N-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide

Compound II-165 was synthesized as shown in Scheme 17.

To a suspension of2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid 12 (500mg, 1.9 mmol) in DCM (4 mL) was added (COCl)₂ (369 mg, 2.9 mmol) and DMF(0.1 mL) and the mixture was stirred for 1 h. MeOH (3 mL) was then addedand the mixture was stirred for 10 m and then concentrated. The residuewas purified using silica gel eluting with EA in PE from 0% to 10% togive methyl 2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetate 90(480 mg) in 93% yield.

To a solution of methyl2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetate 90 (480 mg,1.76 mmol) in DCM (5 mL) at 0° C. was added DAST (1.28 g, 8.82 mmol).The mixture was stirred at RT for overnight. The reaction was quenchedby addition of saturated aqueous NH₄C₁ and the mixture was thenextracted with DCM. The combined organic layers were dried over Na₂SO₄,filtered, and concentrated. The residue was purified using silica geleluting with EA in petroleum from 0% to 20% to give methyl2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetate 91 (450mg) in 87% yield.

To a solution of methyl2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)-acetate 91(450 mg, 1.53 mmol) in THF/H₂O (10 mL/2 mL) at 0° C. was added LiOH.H₂O(128 mg, 3.06 mmol). The mixture was stirred at RT for 4 h, and thenacidified with HCl (1N) (2 mL) and extracted with DCM. The combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified using silica gel eluting with MeOH in DCM from 0%to 10% to give2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid 92(250 mg) in 58% yield. MS (ESI) m/z: 281[M+H]⁺.

To a solution of3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione3 (73 mg, 0.26 mmol) in DCM (2 mL) was added TEA (78 mg, 0.78 mmol),followed by addition of2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetic acid 92(65 mg, 0.31 mmol) and T₃P (197 mg, 0.62 mmol, 50% in EA). The mixturewas stirred for overnight and then concentrated. The residue waspurified by prep-TLC eluting with DCM/MeOH (10:1) to give compoundII-165 (7.4 mg) in 9% yield. MS (ESI) m/z: 542.1 [M+1]⁺; ¹HNMR (400 MHz,DMSO-d₆) δ 10.99 (s, 1H), 9.72 (t, J=5.6 Hz, 1H), 7.90 (s, 1H),7.63-7.57 (m, 4H), 5.01 (dd, J=5.2, 13.2 Hz, 1H), 4.47 (d, J=6.0 Hz,2H), 4.29-4.17 (m, 2H), 2.93-2.84 (m, 1H), 2.61-2.57 (m, 1H), 2.35-2.24(m, 1H), 2.01-1.96 (m, 1H), 1.39-1.36 (m, 2H), 1.17 (s, 2H).

The following compounds were prepared according to a synthetic proceduredescribed herein.

Compound II-2:1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)urea.MS (ESI) m/z: 446.7 [M+H]⁺.

Compound II-3:(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 461.1 [M+H]⁺.

Compound II-4:1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-methoxy-4-methylphenyl)urea.MS (ESI) m/z: 442.8 [M+H]⁺.

Compound II-5:1-(4-chloro-3-(trifluoromethoxy)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 517.0 [M+H]⁺.

Compound II-6:1-(3-chloro-4-methoxyphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 463.1 [M+H]⁺.

Compound II-7:1-(benzo[d][1,3]dioxol-5-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 443.1 [M+H]⁺.

Compound II-8:1-(3-chloro-5-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 501.0 [M+H]⁺.

Compound II-9:1-(3,5-bis(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 535.1 [M+H]⁺.

Compound II-10:1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 447.1 [M+H]⁺.

Compound II-11:1-(3-(dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 456.1 [M+H]⁺.

Compound II-12:N-(5-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)-2-methylphenyl)acetamide.MS (ESI) m/z: 470.2 [M+H]⁺.

Compound II-13:1-(3-chloro-4-(dimethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 476.1 [M+H]⁺.

Compound II-14:N-(2-chloro-4-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)phenyl)acetamide.MS (ESI) m/z: 490.1 [M+H]⁺.

Compound II-15:1-(3-chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)urea.MS (ESI) m/z: 461.1 [M+H]⁺.

Compound II-16:5-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)-2-methylbenzamide.MS (ESI) m/z: 456.1 [M+H]⁺.

Compound II-17:(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 459.8 [M+H]⁺.

Compound II-18:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamide.MS (ESI) m/z: 452.1 [M+H]⁺.

Compound II-19:(S)-1-(3-chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 475.1 [M+H]⁺.

Compound II-20:1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1,3-dimethylurea.MS (ESI) m/z: 475.1 [M+H]⁺.

Compound II-21:1-(3-chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 461.1 [M+H]⁺.

Compound II-22:1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1-methylurea.MS (ESI) m/z: 461.1 [M+H]⁺.

Compound II-23:3-(1-(((3-((3-chloro-4-methylphenyl)amino)propyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione.MS (ESI) m/z: 460.8 [M+H]⁺.

Compound II-24:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide.MS (ESI) m/z: 446.1 [M+H]⁺.

Compound II-25:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-fluorophenyl)acetamide.MS (ESI) m/z: 416.1 [M+H]⁺.

Compound II-26:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methyl-4-morpholinophenyl)urea.MS (ESI) m/z: 498.2 [M+H]⁺.

Compound II-27:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methyl-4-(pyrrolidin-1-yl)phenyl)urea.MS (ESI) m/z: 482.2 [M+H]⁺.

Compound II-28:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide.MS (ESI) m/z: 482.1 [M+H]⁺.

Compound II-29:(S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide.MS (ESI) m/z: 496.1 [M+H]⁺.

Compound II-30:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)acetamide.MS (ESI) m/z: 446.1 [M+H]⁺.

Compound II-31:1-(3-chloro-4-methylphenyl)-3-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)urea.MS (ESI) m/z: 461.1 [M+H]⁺.

Compound II-32:1-(3-chloro-4-methylbenzyl)-3-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)urea.MS (ESI) m/z: 475.1 [M+H]⁺.

Compound II-33:3-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)propanamide.MS (ESI) m/z: 460.1 [M+H]⁺.

Compound II-34:3-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propanamide.MS (ESI) m/z: 460.1 [M+H]⁺.

Compound II-35:3-{2-[(3-chloro-4-methylphenylsulfonylamino)methyl]-6-oxo-3-thia-7-azabicyclo[3.3.0]octa-1,4-dien-7-yl}-2,6-piperidinedione.MS (ESI) m/z: 483.0 [M+H]⁺.

Compound II-36:1-(2,6-dichlorobenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 481.0 [M+H]⁺.

Compound II-37:1-(2,6-dichlorobenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 481.0 [M+H]⁺.

Compound II-38:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2,2-difluoroacetamide.MS (ESI) m/z: 482.0 [M+H]⁺.

Compound II-39:1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)thiourea.MS (ESI) m/z: 463.0 [M+H]⁺.

Compound II-40:1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)urea.MS (ESI) m/z: 483.1 [M+H]⁺.

Compound II-41:4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide.MS (ESI) m/z: 474.1 [M+H]⁺.

Compound II-42:1-(2,6-dichlorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 467.0 [M+H]⁺.

Compound II-43:1-(2,6-dichlorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 467.0 [M+H]⁺.

Compound II-44:3-{3-[(3-chloro-4-methylphenylsulfonylamino)methyl]-8-oxo-2-thia-7-azabicyclo[3.3.0]octa-1(5),3-dien-7-yl}-2,6-piperidinedione.MS (ESI) m/z: 483.1 [M+H]⁺.

Compound II-45:1-(3-(dimethylamino)-4-fluorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 460.1 [M+H]⁺.

Compound II-46:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-hydroxy-4-methylphenyl)urea.MS (ESI) m/z: 429.1 [M+H]⁺.

Compound II-47:1-(3-(diethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 484.2 [M+H]⁺.

Compound II-48:1-(3-(dimethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 442.1 [M+H]⁺.

Compound II-49:1-(3-(dimethylamino)-5-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 456.2 [M+H]⁺.

Compound II-50:1-(3-(dimethylamino)-5-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 510.1 [M+H]⁺.

Compound II-51:1-(3-((dimethylamino)methyl)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 470.2 [M+H]⁺.

Compound II-52:1-(4-(diethylamino)-3-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 484.2 [M+H]⁺.

Compound II-53:1-(3-((dimethylamino)methyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 456.2 [M+H]⁺.

Compound II-54:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-isopropyl-4-methylphenyl)urea.MS (ESI) m/z: 455.2 [M+H]⁺.

Compound II-55:1-(3-(dimethylamino)-4-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 510.1 [M+H]⁺.

Compound II-56:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(isopropyl(methyl)amino)phenyl)urea.MS (ESI) m/z: 470.2 [M+H]⁺.

Compound II-57:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)acetamide.MS (ESI) m/z: 446.1 [M+H]⁺.

Compound II-58:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methoxy-4-methylphenyl)urea.MS (ESI) m/z: 443.1 [M+H]⁺.

Compound II-59:1-(4-(dimethylamino)-3-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 456.1 [M+H]⁺.

Compound II-60:1-(3-(dimethylamino)-5-isopropylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 484.2 [M+H]⁺.

Compound II-61:2-(4-(dimethylamino)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide.MS (ESI) m/z: 441.1 [M+H]⁺.

Compound II-62:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide.MS (ESI) m/z: 454.1 [M+H]⁺.

Compound II-63:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(3-isopropyl-4-methoxyphenyl)acetamide.MS (ESI) m/z: 470.1 [M+H]⁺.

Compound II-64:3-(1-(((5-((3-chloro-4-methylphenyl)amino)pentyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione.MS (ESI) m/z: 489.1 [M+H]⁺.

Compound II-65:3-(2-(((3-((3-chloro-4-methylphenyl)amino)propyl)amino)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dione.MS (ESI) m/z: 461.1 [M+H]⁺.

Compound II-66:1-(3-chloro-4-methylphenethyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 475.1 [M+H]⁺.

Compound II-67:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propanamide.MS (ESI) m/z: 460.1 [M+H]⁺.

Compound II-68:2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide.MS (ESI) m/z: 455.1 [M+H]⁺.

Compound II-69:1-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)methanesulfonamide.MS (ESI) m/z: 482.0 [M+H]⁺.

Compound II-70:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-isopropylphenyl)urea.MS (ESI) m/z: 441.1 [M+H]⁺.

Compound II-71:1-(3-(diethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 470.1 [M+H]⁺.

Compound II-72:1-(3-chloro-4-methylphenyl)-3-((5-(2,5-dioxopyrrolidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 433.0 [M+H]⁺.

Compound II-73:1-(3-chloro-4-methylphenyl)-3-((5-(3-methyl-2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 461.0 [M+H]⁺.

Compound II-74:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-isopropylphenyl)acetamide.MS (ESI) m/z: 440.2 [M+H]⁺.

Compound II-75:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-methylcyclohexyl)acetamide.MS (ESI) m/z: 418.1 [M+H]⁺.

Compound II-76:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(3-(piperidin-1-yl)phenyl)acetamide.MS (ESI) m/z: 481.2 [M+H]⁺.

Compound II-77:2-(3-(2-(dimethylamino)ethoxy)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide.MS (ESI) m/z: 485.1 [M+H]⁺.

Compound II-78:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-morpholinoacetamide.MS (ESI) m/z: 407.1 [M+H]⁺.

Compound II-79:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)acetamide.MS (ESI) m/z: 446.1 [M+H]⁺.

Compound II-80:2-(4-(2-(dimethylamino)ethoxy)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide.MS (ESI) m/z: 485.2 [M+H]⁺.

Compound II-81:(3-(24(3-(3-(dimethylamino)-4-methylphenyl)ureido)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methylD-valinate. MS (ESI) m/z: 585.3 [M+H]⁺.

Compound II-82:(3-(24(3-(3-chloro-4-methylphenyl)ureido)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methylD-valinate. MS (ESI) m/z: 576.1 [M+H]⁺.

Compound II-83:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-morpholinophenyl)acetamide.MS (ESI) m/z: 483.1 [M+H]⁺.

Compound II-84:4-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide.MS (ESI) m/z: 482.1 [M+H]⁺.

Compound II-85:4-(4-(dimethylamino)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide.MS (ESI) m/z: 469.1 [M+H]⁺.

Compound II-86:4-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-methylbutanamide.MS (ESI) m/z: 496.2 [M+H]⁺.

Compound II-87:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide.MS (ESI) m/z: 474.1 [M+H]⁺.

Compound II-88:2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(p-tolyl)acetamide.MS (ESI) m/z: 427.0 [M+H]⁺.

Compound II-89:2-amino-2-(3-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamide.MS (ESI) m/z: 447.0 [M+H]⁺.

Compound II-90:(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 447.0 [M+H]⁺.

Compound II-91:(R)-1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 447.0 [M+H]⁺.

Compound II-92:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propanamide.MS (ESI) m/z: 468.1 [M+H]⁺.

Compound II-93:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(pyrrolidin-1-yl)phenyl)acetamide.MS (ESI) m/z: 467.1 [M+H]⁺.

Compound II-94:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-methylbutanamide.MS (ESI) m/z: 496.2 [M+H]⁺.

Compound II-95:2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-methylbutanamide.MS (ESI) m/z: 488.1 [M+H]⁺.

Compound II-96:1-(3-(dimethylamino)-4-ethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 470.1 [M+H]⁺.

Compound II-97:1-(3-(diethylamino)-4-fluorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 488.1 [M+H]⁺.

Compound II-98:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(4-methyl-3-(pyrrolidin-1-yl)phenyl)urea.MS (ESI) m/z: 482.1 [M+H]⁺.

Compound II-99:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(pyrrolidin-1-yl)phenyl)urea.MS (ESI) m/z: 468.1 [M+H]⁺.

Compound II-100:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(ethyl(methyl)amino)-4-methylphenyl)urea.MS (ESI) m/z: 470.1 [M+H]⁺.

Compound II-101:4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-methylbutanamide.MS (ESI) m/z: 489.1 [M+H]⁺.

Compound II-102:(2S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propanamide.MS (ESI) m/z: 460.0 [M+H]⁺.

Compound II-103:(2R)-2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propanamide.MS (ESI) m/z: 460.0 [M+H]⁺.

Compound II-104:(S)-4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-dimethylbutanamide.MS (ESI) m/z: 502.1 and 504.1 [M+H]⁺.

Compound II-105: di-tert-butyl((3-(2-((3-(3-(dimethylamino)-4-methylphenyl)ureido)-methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methyl)phosphate. MS (ESI) m/z: 678.2 [M+H]⁺.

Compound II-106:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-isopropylphenyl)-3-methylbutanamide.MS (ESI) m/z: 482.2 [M+H]⁺.

Compound II-107:N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(perfluorophenyl)acetamide.MS (ESI) m/z: 488.0 [M+H]⁺.

Compound II-108:2-(dimethylamino)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(2-fluorophenyl)acetamide.MS (ESI) m/z: 459.1 [M+H]⁺.

Compound II-109:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-phenylbutanamide.MS (ESI) m/z: 426.1 [M+H]⁺.

Compound II-110:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-phenylthiourea.MS (ESI) m/z: 415.0 [M+H]⁺.

Compound II-111:1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)thiourea.MS (ESI) m/z: 498.9 [M+H]⁺.

Compound II-112:2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-propoxyphenyl)acetamide.MS (ESI) m/z: 470.9 [M+H]⁺.

Compound II-113:2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-hydroxyphenyl)acetamide.MS (ESI) m/z: 428.9 [M+H]⁺.

Compound II-114:1-(3-(dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 470.1 [M+H]⁺.

Compound II-115:4-(4-(dimethylamino)-3-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamide.MS (ESI) m/z: 483.1 [M+H]⁺.

Compound II-116:N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(3-fluoro-2-methoxyphenyl)acetamide.MS (ESI) m/z: 446.1 [M+H]⁺.

Compound II-117:4-bromo-2,5-dichloro-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiophene-3-sulfonamide.MS (ESI) m/z: 573.8 [M+H]⁺.

Compound II-118: methyl5-chloro-3-(N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)sulfamoyl)thiophene-2-carboxylate.MS (ESI) m/z: 517.9 [M+H]⁺.

Compound II-119:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-methyl-1,2,3-thiadiazole-5-carboxamide.MS (ESI) m/z: 406.0 [M+H]⁺.

Compound II-120:N-(5-(N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)sulfamoyl)-4-methylthiazol-2-yl)acetamide.MS (ESI) m/z: 498.2 [M+H]⁺.

Compound II-121:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,3,4,5,6-pentafluorobenzenesulfonamide.MS (ESI) m/z: 509.9 [M+H]⁺.

Compound II-122:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide.MS (ESI) m/z: 424.0 [M+H]⁺.

Compound II-123:1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(2,3,5,6-tetrachlorophenyl)thiourea.MS (ESI) m/z: 552.9 and 554.9 [M+H]⁺.

Compound II-124:4-(tert-butyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)benzenesulfonamide.MS (ESI) m/z: 476.1 [M+H]⁺.

Compound II-125: methyl3-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)thiophene-2-carboxylate.MS (ESI) m/z: 463.0 [M+H]⁺.

Compound II-126:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiazole-2-carboxamide.MS (ESI) m/z: 391.0 [M+H]⁺.

Compound II-127:1-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)cyclopropane-1-carboxamide.MS (ESI) m/z: 480.1 [M+H]⁺.

Compound II-128:1-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)methanesulfonamide.MS (ESI) m/z: 490.1 [M+H]⁺.

Compound II-129:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamide.MS (ESI) m/z: 490.1 [M+H]⁺.

Compound II-130:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)furan-3-sulfonamide.MS (ESI) m/z: 410.0 [M+H]⁺.

Compound II-131:4-(tert-butyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)benzenesulfonamide.MS (ESI) m/z: 490.1 [M+H]⁺.

Compound II-132:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-hydroxyacetamide.MS (ESI) m/z: 470.1 [M+H]⁺.

Compound II-133:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3,3,3-trifluoro-2-hydroxypropanamide. MS (ESI) m/z: 538.1 [M+H]⁺.

Compound II-134:3-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)furan-2-carboxamide.MS (ESI) m/z: 452.0 [M+H]⁺.

Compound II-135:4-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(trifluoromethoxy)benzenesulfonamide.MS (ESI) m/z: 583.9 [M+H]⁺.

Compound II-136:2-chloro-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)thiazole-5-carboxamide.MS (ESI) m/z: 424.9 and 426.9 [M+H]⁺.

Compound II-137: methyl2-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)thiophene-3-carboxylate.MS (ESI) m/z: 463.0 [M+H]⁺.

Compound II-138:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(6-morpholinopyridin-3-yl)urea.MS (ESI) m/z: 485.1 [M+H]⁺.

Compound II-139:1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 417.0 [M+H]⁺.

Compound II-140:N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3,5-dimethylisoxazole-4-carboxamide.MS (ESI) m/z: 403.2 [M+H]⁺.

Compound II-141:N-(5-(N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)sulfamoyl)-4-methylthiazol-2-yl)acetamide.MS (ESI) m/z: 498.0 [M+H]⁺.

Compound II-142:N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2,5-dimethylfuran-3-sulfonamide.MS (ESI) m/z: 438.0 [M+H]⁺.

Compound II-143:5-(N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)sulfamoyl)-2-methoxy-N,N-dimethylbenzamide.MS (ESI) m/z: 521.1 [M+H]⁺.

Compound II-144:N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(propylthio)nicotinamide.MS (ESI) m/z: 459.0 [M+H]⁺.

Compound II-145:1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-phenoxypropyl)urea.MS (ESI) m/z: 457.2 [M+H]⁺.

Compound II-146:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-(4-morpholinophenyl)butanamide.MS (ESI) m/z: 511.1 [M+H]⁺.

Compound II-147:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3,3,3-trifluoropropanamide.MS (ESI) m/z: 522.3 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),8.95 (s, 1H), 7.87 (s, 1H), 7.42 (m, 4H), 5.00 (dd, 1H), 4.46 (m, 3H),4.18 (m, 2H), 2.29 (m, 1H), 2.89 (m, 1H), 2.56 (s, 1H), 2.33 (m, 1H),1.91 (m, 1H), 1.27 (s, 9H).

Compound II-148:1-(4-(tert-butyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea.MS (ESI) m/z: 455.1 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.97 (s, 1H),8.55 (s, 1H), 7.86 (s, 1H), 7.31-7.22 (m, 4H), 6.72 (t, J=5.2 Hz, 1H),5.00 (dd, J=4.8, 13.2 Hz, 1H), 4.43-4.20 (m, 4H), 2.92-2.83 (m, 1H),2.60-2.56 (m, 1H), 2.34-2.24 (m, 1H), 1.99-1.96 (m, 1H), 1.24 (s, 9H).

Compound II-150:1-(2,3-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 427.1 [M+H]⁺.

Compound II-151:1-(2,4-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 427.1 [M+H]⁺.

Compound II-152:1-(2,5-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 427.1 [M+H]⁺.

Compound II-153:1-([1,1′-biphenyl]-4-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 475.1 [M+H]⁺.

Compound II-154:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(4-methoxyphenyl)urea.MS (ESI) m/z: 429.1 [M+H]⁺.

Compound II-155:1-(4-cyanophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 424.0 [M+H]⁺.

Compound II-156:1-(2,6-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 427.0 [M+H]⁺.

Compound II-157:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-phenethylthiourea.MS (ESI) m/z: 443.0 [M+H]⁺.

Compound II-158:1-(2-trifluoromethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 467.0 [M+H]⁺.

Compound II-159:1-(3-cyanophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 424.1 [M+H]⁺.

Compound II-160:1-(4-chloro-2-trifluoromethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 501.0 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H),8.10 (s, 1H), 7.96 (d, J=8.8 Hz, 1H), 7.77 (t, J=5.6 Hz, 1H), 7.66-7.68(m, 2H), 7.14 (s, 1H), 4.98 (dd, J=4.8, 13.2 Hz, 1H), 4.56 (d, J=5.6 Hz,2H), 4.20-4.37 (m, 2H), 2.84-2.89 (m, 1H), 2.55-2.60 (m, 1H), 2.32-2.36(m, 1H), 1.97-2.00 (m, 1H).

Compound II-161:1-(2,4,6-trimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 441.1 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.94 (s, 1H),7.56 (s, 1H), 7.06 (s, 1H), 6.85 (s, 2H), 6.70 (brs, 1H), 4.98 (dd,J=4.8, 13.2 Hz, 1H), 4.47 (d, J=5.6 Hz, 2H), 4.17-4.35 (m, 2H),2.84-2.93 (m, 1H), 2.55-2.59 (m, 1H), 2.36-2.38 (m, 1H), 2.32 (s, 1H),2.28 (s, 6H), 1.96-2.00 (m, 1H).

Compound II-162:1-(3,5-dimethoxyphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urea.MS (ESI) m/z: 459.1 [M+H]⁺.

Compound II-163:1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(naphthalen-1-yl)urea.MS (ESI) m/z: 449.0 [M+H]⁺.

Compound II-164:N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamide.MS (ESI) m/z: 536.1 [M+H]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.9 (s, 1H),9.68 (t, 1H), 7.35-7.68 (m, 7H), 5.09 (dd, 1H), 4.25-4.46 (m, 4H), 2.92(m, 1H), 2.64 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H).

Example B1 Protein Degradation Assays

MV-4-11 cells were grown in RPMI 1640 media supplemented with 10% fetalbovine serum, streptomycin, and penicillin. The cells were cultured atapproximately 10⁶ cells per mL and incubated in DMSO or a compound for6-8 h. Whole cell extracts were prepared using aradioimmunoprecipitation assay (RIPA) buffer. Briefly, 3×10⁶ cells werewashed once in PBS, and the cell pellets were resuspended in the RIPAbuffer and incubated for 15 min on ice. Cells debris was removed bycentrifugation and the cleared whole cell lysates were transferred tonew tubes for further analysis.

For Western blot analysis, whole cell protein extracts were separated on4-12% SDS-polyacrylamide gels, transferred to nitrocellulose, and probedwith primary antibodies. Membranes were subsequently washed and probedwith IRDYE® secondary antibodies. The signal was detected using anODYSSEY® Imaging System.

The following antibodies were used in the assays described herein:anti-eRF3/GSPT1: Abcam, ab126090 (Cambridge, Mass.); anti-Ikaros: Abcam,ab191394 (Cambridge, Mass.); anti-CK1α: Abcam, ab108296 (Cambridge,Mass.); β-actin (8H10D10) mouse monoclonal antibody: Cell SignalingTechnology, #3700 (Danvers, Mass.); IRDYE® 680RD goat anti-rabbitantibody: LI-COR, 926-68071 (Lincoln, Nebr.); and IRDYE® 800CW goatanti-mouse antibody: LI-COR, 926-32210 (Lincoln, Nebr.).

The protein degradation results are summarized in Table 1, wherein Arepresents a value no less than 80%, B represents a value less than 80%but no less than 50%, C represents a value less than 50% but no lessthan 25%, and D represents a value less than 25% protein degradation ata compound concentration of 0.1 μM.

TABLE 1 Protein Degradation Compound IKAROS CK1α GSPT1 I-1 A B B I-2 A BA I-3 A A B I-4 A C I-5 A C A II-1 B

Example B2 Cytokine Modulation Assays

Frozen primary blood mononuclear cells (PBMCs) or frozen CD14+ mobilizedperipheral blood monocytes were quick thawed, washed once with RPMI-1640(10% FBS/1% Pen-Strep), and plated in 96 well plates at 200,000 cellsper well. The cells were pretreated with DMSO only or with a compoundfor 1 h and then induced with 100 ng/mL lipopolysaccharide (LPS) for18-24 h. The supernatant was analyzed for IL-1β, IL-6, and TNFα usingMeso Scale assays. The negative control wells were treated with DMSO.The results are summarized in Table 2, wherein A represents a value noless than 80%, B represents a value less than 80% but no less than 50%,C represents a value less than 50% but no less than 25%, and Drepresents a value less than 25% inhibition at the specified compoundconcentration.

TABLE 2 Cytokine Inhibition IL-1β IL-6 TNF-α Compound 0.1 μM 1 μM 0.1 μM0.1 μM 1 μM I-1 A B A I-2 I-3 A A C A A I-4 A A A A I-5 II-1 C C

For the IL-2 analysis, 96 well plates were precoated with 1 μg/mLanti-human CD3 antibody (OKT3, eBioscience Inc., San Diego, Calif.).After washed with PBS, the compound was added (50 μL/well), followed byaddition of PBMCs diluted at 3-4 million cells/mL (150 μL/well). Theplates were incubated for 24 h and the supernatants were collected forIL-2 analysis. IL-2 activity was measured as fold difference from theDMSO control. At a concentration of 0.01 μM, compounds I-1 and I-3stimulated IL-2 production with 3.7 and 3.9 fold change, respectively,over the DMSO control.

Example B3 Cell Viability Assays

MOLM-13 cells were cultured in RPMI 1640 media supplemented with 10%fetal bovine serum, streptomycin, and penicillin. The cells were platedin white walled 96-well plates at 2,500 cells/well. The cells wereincubated in DMSO (control) or an indicated compound for 3 days at 37°C. and 5% CO₂. Following the incubation period, 100 (IL ofCELLTITER-GLO® (CTG) reagent was added to each well. Following a 10minutes incubation with shaking, luminescence was measured using anENVISION® Multimode plate reader. Antiproliferative activity ofcompounds in the MOLM-13 cell viability assay is summarized in Table 3,wherein A represents a value no less than 80%, B represents a value lessthan 80% but no less than 50%, C represents a value less than 50% but noless than 25%, and D represents a value less than 25% inhibition at aconcentration of 1 μM.

TABLE 3 Antiproliferative Activity Compound Activity I-1 A I-2 A I-3 AI-4 A I-5 A I-6 C I-7 D I-8 D I-9 D I-10 A I-11 D I-12 D I-13 D I-14 CI-15 C I-16 D I-17 D I-18 D I-19 A I-20 D I-21 C I-22 D I-23 D I-24 CI-25 D I-26 D I-27 A I-28 A I-29 A I-30 A I-31 D I-32 A I-33 A I-34 DI-35 D I-36 C I-37 A I-38 D I-39 A I-40 D I-41 A I-42 B I-43 D I-44 AI-45 B I-46 C I-47 D I-48 D I-49 B I-50 D I-51 D I-52 C I-53 A I-54 AI-55 A I-56 D I-57 D I-58 B I-59 C I-60 B I-61 D I-62 A I-64 A I-65 DI-66 D I-67 C I-68 D I-72 D I-73 D I-74 D I-75 C I-76 D I-77 D I-78 CI-79 D I-80 D I-81 C I-82 C I-83 A I-84 C I-85 B I-86 B I-87 C I-88 DI-89 A I-90 D I-91 A I-92 B I-93 A I-94 D I-95 A I-96 D I-103 D I-104 AI-105 D I-106 D II-1 A II-20 D II-21 B II-22 B II-23 D II-24 D II-25 DII-26 D II-27 D II-28 D II-29 D II-30 D II-31 A II-32 A II-33 D II-34 AII-35 C II-36 B II-37 A II-38 D II-39 A II-40 D II-41 C II-42 D II-43 CII-44 D II-45 A II-46 C II-47 A II-48 A II-49 A II-50 A II-51 D II-52 DII-53 D II-54 A II-55 A II-56 A II-57 B II-58 A II-59 D II-60 A II-61 DII-62 C II-63 A II-64 D II-65 D II-66 D II-67 D II-68 C II-69 B II-70 AII-71 A II-72 C II-73 D II-74 D II-75 D II-76 A II-77 D II-78 D II-79 DII-80 D II-81 A II-82 A II-83 D II-84 D II-85 D II-86 D II-87 D II-88 DII-89 D II-90 A II-91 A II-92 D II-93 D II-94 D II-95 C II-96 A II-97 AII-98 A II-99 A II-100 A II-101 D II-102 D II-103 D II-104 D II-105 DII-106 D II-108 D II-112 D II-113 D II-114 C II-115 D II-116 D II-123 DII-124 D II-127 C II-128 A II-129 D II-131 D II-132 C II-133 D II-145 BII-146 D II-147 D II-148 A II-149 A II-164 A II-165 D

THLE-2 cells were cultured using BEGM™ BULLETKIT™ supplemented with 10%fetal bovine serum, streptomycin, and penicillin. The cells were platedin white walled 96-well plates at 5,000 cells/well. After the cells wereincubated in DMSO (control) or a compound for 3 days at 37° C. and 5%CO₂, 100 μL of CELLTITER-GLO® (CTG) was added to each well. Following a10 minutes incubation with shaking, luminescence was measured using anENVISION® Multimode plate reader. In this example, compound II-1 wascompared to reference compound A:

The THLE-2 IC₅₀ for compound II-1 and reference compound A are 8.9 μMand 0.80 μM, respectively.

The examples set forth above are provided to give those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the claimed embodiments, and are not intended to limit thescope of what is disclosed herein. Modifications that are obvious topersons of skill in the art are intended to be within the scope of thefollowing claims. All publications, patents, and patent applicationscited in this specification are incorporated herein by reference as ifeach such publication, patent or patent application were specificallyand individually indicated to be incorporated herein by reference.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is selectedfrom the group consisting of

each X is independently CH₂ or C(═O); Y is C(═O),C(═O)—(CR^(6a)R^(6b))_(n1), C(═S), or C(═S)—(CR^(6c)R^(6d))_(n2); R² isH, deuterium, optionally substituted C₁-C₆ alkyl, optionally substitutedC₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted 3 to 10 membered heterocyclyl, or optionally substituted 5to 10 membered heteroaryl; ring A is C₆-C₁₀ aryl, 5 to 10 memberedheteroaryl, C₃-C₈ carbocyclyl, or 3 to 10 membered heterocyclyl, eachoptionally substituted with one or more R^(A); R^(3a), R^(3b), R^(3c),R^(3d), R^(3e), and R^(3f) are each independently H, deuterium,hydroxyl, halogen, cyano, nitro, optionally substituted C₁-C₆ alkyl,C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a), —O(CH₂)_(t)—NR^(7a)R^(8a),—C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c), —OR⁹, —SR^(10a), —C(O)OR^(10b),—C(O)R^(11a), —NR^(7d)C(O)R^(11b), —S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d),(C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionallysubstituted C₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 3 to 10 membered heterocyclyl, or optionallysubstituted 5 to 10 membered heteroaryl; each R^(3g) is independentlydeuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a), —O(CH₂)_(t)—NR^(7a)R^(8a),—C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c), —OR⁹, —SR^(10a), —C(O)OR^(10b),—C(O)R^(11a), —NR^(7d)C(O)R^(11b), —S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d),(C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionallysubstituted C₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 3 to 10 membered heterocyclyl, or optionallysubstituted 5 to 10 membered heteroaryl; each R⁴ is independently H,deuterium, halogen, or optionally substituted C₁-C₆ alkyl; each R⁵ isindependently H, deuterium, C₁-C₆ alkyl,

each R^(6a), R^(6b), R^(6e), R^(6d), R¹⁴, and R¹⁵ is independently H,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(6a) andR^(6b) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R^(6c) and R^(6d) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B); eachR^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c), R¹⁶, andR¹⁷ is independently H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl, oroptionally substituted C₃-C₈ carbocyclyl; or R^(7a) and R^(8a) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R^(7b) and R^(8b) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R^(7c) and R^(8c) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; wherein each of C₆-C₁₀ aryl,C₇-C₁₄ aralkyl, C₃-C₈ carbocyclyl, and 3 to 7 membered heterocyclyl isoptionally substituted with one or more R^(B); each R⁹ is independentlyoptionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₆-C₁₀ aryl, optionally substituted 5 to 10 membered heteroaryl,optionally substituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10membered heterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; eachof R^(10a), R^(10b), R¹², and R¹³ is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(11a),R^(11b), R^(11c), and R^(11d) is independently optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(A) isindependently halogen, cyano, nitro, hydroxyl, optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B); eachR^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, (C₁-C₆alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl,halogen, or cyano; or two geminal R^(B) form oxo; m is an integer of 0,1, 2, 3, 4, or 5; n1 and n2 are each independently an integer of 0, 1, 2or 3; each p is independently an integer of 0, 1, or 2; and each t isindependently an integer of 0, 1, 2, 3, 4, or
 5. 2. The compound ofclaim 1, being a compound of Formula (Ia):

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim1, being a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim1, being a compound of Formula (Ic):

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, being a compound of Formula (Id):

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, being a compound of Formula (Ie):

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, being a compound of Formula (If):

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, being a compound of Formula (Ig):

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1, being a compound of Formula (Ih):

or a pharmaceutically acceptable salt thereof.
 10. The compound of anyone of claims 1 to 9, wherein Y is (C═O)—(CH₂)_(n1).
 11. The compound ofany one of claims 1 to 10, wherein Y is C(═O), C(═O)CH₂, or C(═O)CH₂CH₂.12. A compound of Formula (III):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein: R¹ isselected from the group consisting of

each X is independently CH₂ or C(═O); R^(Z) is —NR^(7a)R^(8a) or ring A;and ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, each optionallysubstituted with one or more R^(A); R² is H, deuterium, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 3 to 10membered heterocyclyl, or optionally substituted 5 to 10 memberedheteroaryl; R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) are eachindependently H, deuterium, hydroxyl, halogen, cyano, nitro, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;each R^(3g) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl; each R⁵ is independently H, deuterium, C₁-C₆alkyl,

each R^(6a), R^(6b), R^(6c), R^(6d), R¹⁴, and R¹⁵ is independently H,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(6a) andR^(6b) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R⁶ and R^(6d) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B); eachR^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c), R¹⁶ andR¹⁷ is independently H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl, oroptionally substituted C₃-C₈ carbocyclyl; or R^(7a) and R^(8a) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R^(7b) and R^(8b) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R^(7c) and R^(8c) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R¹⁶ and R¹⁷ together withthe nitrogen atom to which they are attached form optionally substituted3 to 7 membered heterocyclyl; wherein each of C₆-C₁₀ aryl, C₇-C₁₄aralkyl, C₃-C₈ carbocyclyl, and 3 to 7 membered heterocyclyl isoptionally substituted with one or more R^(B); each R⁹ is independentlyoptionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₆-C₁₀ aryl, optionally substituted 5 to 10 membered heteroaryl,optionally substituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10membered heterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; eachof R^(10a), R^(10b), R¹², and R¹³ is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(11a),R^(11b), R^(11c), and R^(11d) is independently optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(A) isindependently halogen, cyano, nitro, hydroxyl, optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B); eachR^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl,halogen, or cyano; or two geminal R^(B) form oxo; m is an integer of 0,1, 2, 3, 4, or 5; n1 is an integer of 0, 1, 2, or 3; each p isindependently an integer of 0, 1, or 2; and each t is independently aninteger of 0, 1, 2, 3, 4, 5, 6, 7, or
 8. 13. The compound of claim 12,being a compound of Formula (IIIa):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 14. The compoundof claim 12, being a compound of Formula (IIIb):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 15. The compoundof claim 12, being a compound of Formula (IIIc):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 16. The compoundof claim 12, being a compound of Formula (IIId):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 17. The compoundof claim 12, being a compound of Formula (IIIe):

or a pharmaceutically acceptable salt thereof.
 18. The compound of claim12, being a compound of Formula (IIIf):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 19. The compoundof claim 12, being a compound of Formula (IIIg):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 20. The compoundof claim 12, being a compound of Formula (IIIh):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 21. The compoundof claim 12, being a compound of Formula (IIIi):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 22. A compound ofFormula (IV):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein: R¹ isselected from the group consisting of

each X is independently CH₂ or C(═O); R^(Z) is —NR^(7a)R^(8a) or ring A;and ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, each optionallysubstituted with one or more R^(A); R² is H, deuterium, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 3 to 10membered heterocyclyl, or optionally substituted 5 to 10 memberedheteroaryl; R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) are eachindependently H, deuterium, hydroxyl, halogen, cyano, nitro, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;each R^(3g) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl; each R⁵ is independently H, deuterium, C₁-C₆alkyl,

each R^(6a), R^(6b), R^(6e), R^(6d), R¹⁴, and R¹⁵ is independently H,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(6a) andR^(6b) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R^(6c) and R^(6d) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B); eachR^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c), R¹⁶, andR¹⁷ is independently H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl, oroptionally substituted C₃-C₈ carbocyclyl; or R^(7a) and R^(8a) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R^(7b) and R^(8b) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R^(7c) and R^(8c) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R¹⁶ and R¹⁷ together withthe nitrogen atom to which they are attached form optionally substituted3 to 7 membered heterocyclyl; wherein each of C₆-C₁₀ aryl, C₇-C₁₄aralkyl, C₃-C₈ carbocyclyl, and 3 to 7 membered heterocyclyl isoptionally substituted with one or more R^(B); each R⁹ is independentlyoptionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₆-C₁₀ aryl, optionally substituted 5 to 10 membered heteroaryl,optionally substituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10membered heterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; eachof R^(10a), R^(10b), R¹², and R¹³ is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(11a),R^(11b), R^(11c), and R^(11d) is independently optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(A) isindependently halogen, cyano, nitro, hydroxyl, optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B); eachR^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl,halogen, or cyano; or two geminal R^(B) form oxo; m is an integer of 0,1, 2, 3, 4, or 5; n1 is an integer of 0, 1, 2, or 3; each p isindependently an integer of 0, 1, or 2; and each t is independently aninteger of 0, 1, 2, 3, 4, 5, 6, 7, or
 8. 23. A compound of Formula (V):

or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture oftwo or more diastereomers, a tautomer, a mixture of two or moretautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof; wherein: R¹ isselected from the group consisting of

each X is independently CH₂ or C(═O); R^(Z) is —NR^(7a)R^(8a) or ring A;and ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, each optionallysubstituted with one or more R^(A); R² is H, deuterium, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl,optionally substituted C₆-C₁₀ aryl, optionally substituted 3 to 10membered heterocyclyl, or optionally substituted 5 to 10 memberedheteroaryl; R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) are eachindependently H, deuterium, hydroxyl, halogen, cyano, nitro, optionallysubstituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), s (O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;each R^(3g) is independently deuterium, hydroxyl, halogen, cyano, nitro,optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, optionally substituted C₃-C₈ carbocyclyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted 5 to 10 membered heteroaryl;each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl; each R⁵ is independently H, deuterium, C₁-C₆alkyl,

each R^(6a), R^(6b), R^(6c), R^(6d), R¹⁴, and R¹⁵ is independently H,substituted or unsubstituted amino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; or R^(6a) andR^(6b) together with the carbon atom to which they are attached form aC₃-C₈ carbocyclyl; or R^(6c) and R^(6d) together with the carbon atom towhich they are attached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈carbocyclyl is optionally substituted with one or more R^(B); eachR^(7a), R^(7b), R^(7c), R^(7d), R^(7e), R^(8a), R^(8b), R^(8c), R¹⁶, andR¹⁷ is independently H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl, oroptionally substituted C₃-C₈ carbocyclyl; or R^(7a) and R^(8a) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R^(7b) and R^(8b) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R^(7c) and R^(8c) togetherwith the nitrogen atom to which they are attached form optionallysubstituted 3 to 7 membered heterocyclyl; or R¹⁶ and R¹⁷ together withthe nitrogen atom to which they are attached form optionally substituted3 to 7 membered heterocyclyl; wherein each of C₆-C₁₀ aryl, C₇-C₁₄aralkyl, C₃-C₈ carbocyclyl, and 3 to 7 membered heterocyclyl isoptionally substituted with one or more R^(B); each R⁹ is independentlyoptionally substituted C₁-C₆ alkyl, optionally substituted C₂-C₆alkenyl, optionally substituted C₂-C₆ alkynyl, optionally substitutedC₆-C₁₀ aryl, optionally substituted 5 to 10 membered heteroaryl,optionally substituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10membered heterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; eachof R^(10a), R^(10b)R¹², and R¹³ is independently H, optionallysubstituted C₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl,optionally substituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀aryl, optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(11a),R^(11b), R^(11c), and R^(11d) is independently optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(A) isindependently halogen, cyano, nitro, hydroxyl, optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B); eachR^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl,halogen, or cyano; or two geminal R^(B) form oxo; m is an integer of 0,1, 2, 3, 4, or 5; n1 is an integer of 0, 1, 2, or 3; each p isindependently an integer of 0, 1, or 2; and each t is independently aninteger of 0, 1, 2, 3, 4, 5, 6, 7, or
 8. 24. The compound of any one ofclaims 12 to 23, wherein R^(Z) is ring A.
 25. The compound of any one ofclaims 1 to 24, wherein X is CH₂.
 26. The compound of any one of claims1 to 24, wherein X is C(═O).
 27. The compound of any one of claims 1 to26, wherein p is
 1. 28. The compound of any one of claims 1 to 26,wherein p is
 2. 29. The compound of any one of claims 1 to 28, whereineach of R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), and R^(3f) is H.
 30. Thecompound of any one of claims 1, 10 to 12, and 22 to 29, wherein R¹ is


31. The compound of any one of claims 1, 10 to 12, and 22 to 29, whereinR¹ is

optionally substituted with one R^(3g).
 32. The compound of any one ofclaims 1, 10 to 12, and 22 to 29, wherein R¹ is

optionally substituted with one R^(3g).
 33. The compound of any one ofclaims 1, 8 to 12, 19 to 29, 31, and 32, wherein R^(3g) is halo, C₁-C₆alkyl, or C₁-C₆ haloalkyl.
 34. The compound of claim 33, wherein R^(3g)is fluoro or methyl.
 35. The compound of any one of claims 1 to 34,wherein R⁴ is H.
 36. The compound of any one of claims 1 to 35, whereinR⁵ is H.
 37. The compound of any one of claims 1 to 35, wherein R⁵ is


38. The compound of claim 37, wherein R⁵ is valyloxymethyl.
 39. Thecompound of any one of claims 1 to 38, wherein R² is H.
 40. The compoundof any one of claims 1 to 39, wherein ring A is C₆-C₁₀ aryl, 5 to 10membered heteroaryl, C₃-C₈ carbocyclyl, or 3 to 10 memberedheterocyclyl, each of which is optionally substituted with one, two, orthree substituents R^(A).
 41. The compound of any one of claims 1 to 40,wherein ring A is C₆-C₁₀ aryl, optionally substituted with one, two, orthree substituents R^(A).
 42. The compound of any one of claims 1 to 40,wherein ring A is phenyl, optionally substituted with one, two, or threesubstituents R^(A).
 43. The compound of any one of claims 1 to 40,wherein ring A is selected from the group consisting of pyridyl,thienyl, furyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, and thiadiazolyl, each optionallysubstituted with one, two, or three R^(A).
 44. The compound of any oneof claims 1 to 43, wherein each substituent R^(A) is independentlyhalogen, cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,—(CH₂)_(t)—NR^(7a)R^(8a), —NR^(7d)C(O)R^(11b), phenyl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, where each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B).
 45. Thecompound of any one of claims 1 to 44, wherein ring A is phenyl,naphthyl, thienyl, pyridyl, piperidinyl, or cyclohexyl, each of which isoptionally substituted with one, two, or three substituents R^(A),wherein each substituent R^(A) is independently cyano, fluoro, chloro,bromo, methyl, trifluoromethyl-ethyl, trifluoromethyl,dimethylaminomethyl, morpholinylmethyl, propyl, butyl, hydroxyl-butyl,cyclopropyl, methylcyclopropyl, trifluoromethyl-cyclopropyl, phenyl,methyl-piperidinyl, hydroxyl, methoxy, dimethylamino, or acetamido. 46.The compound of any one of claims 1 to 44, wherein ring A is phenyl,cyanophenyl, fluorophenyl, chlorophenyl, bromophenyl, methylphenyl,(1-trifluoromethylethyl)-phenyl, trifluoromethylphenyl,dimethylaminomethylphenyl, morpholin-4-ylmethylphenyl, isopropylphenyl,sec-butylphenyl, tert-butylphenyl, (hydroxyl-tert-butyl)phenyl,cyclopropylphenyl, (1-methylcyclopropyl)phenyl,(1-trifluoromethylcyclopropyl)-phenyl, phenylphenyl,(1-methylpiperidin-4-yl)phenyl, hydroxylphenyl, methoxyphenyl,dimethylaminophenyl, acetamidophenyl, difluorophenyl, dichlorophenyl,chloro-methylphenyl, methyl-tert-butylphenyl, dimethylphenyl,trimethylphenyl, trimethoxyphenyl, dimethyl-tert-butylphenyl,dimethylamino-methylphenyl, naphthyl, thienyl, isopropylthienyl,pyridyl, tert-butylcyclohexyl, piperidinyl, or tert-butylpiperidinyl.47. The compound of any one of claims 1 to 44, wherein ring A is phenyl,4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,3-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl,4-(1-trifluoromethylethyl)-phenyl, 4-trifluoromethylphenyl,4-dimethylaminomethylphenyl, 4-morpholin-4-ylmethylphenyl,4-isopropylphenyl, 4-sec-butylphenyl, 3-tert-butylphenyl,4-tert-butylphenyl, 4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,4-(1-methyl-cyclopropyl)phenyl, 4-(1-trifluoromethylcyclopropyl)phenyl,4-phenylphenyl, 4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl,2,6-dimethyl-4-tert-butylphenyl, 3-dimethylamino-4-methylphenyl,2-naphthyl, thien-2-yl, 5-isopropylthien-2-yl, 4-pyridyl,4-tert-butylcyclohexyl, piperdin-4-yl, or 4-tert-butylpiperidin-1-yl.48. The compound of any one of claims 1 to 44, wherein ring A is phenyl,4-cyanophenyl, 2-fluorophenyl, 3-fluorophenyl, 3-chlorophenyl,4-trifluoromethylphenyl, 3-tert-butylphenyl, 4-tert-butylphenyl,4-(1-trifluoromethylcyclopropyl)phenyl, 3-methoxyphenyl,4-methoxyphenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl,2,6-dimethyl-4-tert-butylphenyl, 2-naphthyl, 5-isopropylthien-2-yl,4-pyridyl, 4-tert-butylcyclohexyl, or 4-tert-butylpiperidin-1-yl. 49.The compound of any one of claims 1 to 48, wherein: X is CH₂ or C(═O); Yis C(═O), CH₂C(O), CH₂CH₂C(O); ring A is phenyl, 4-cyanophenyl,2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl,4-chlorophenyl, 4-bromophenyl, 4-methylphenyl,4-(1-trifluoromethylethyl)-phenyl, 4-trifluoromethylphenyl,4-dimethylaminomethylphenyl, 4-morpholin-4-ylmethylphenyl,4-isopropylphenyl, 4-sec-butylphenyl, 3-tert-butylphenyl,4-tert-butylphenyl, 4-(hydroxyl-tert-butyl)phenyl, 4-cyclopropylphenyl,4-(1-methylcyclopropyl)phenyl, 4-(1-trifluoromethylcyclopropyl)phenyl,4-phenylphenyl, 4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl,3-methoxyphenyl, 4-methoxyphenyl, 4-dimethylaminophenyl,4-acetamidophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl,3-chloro-4-methylphenyl, 3-methyl-4-tert-butylphenyl,3,5-dimethylphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl,2,6-dimethyl-4-tert-butylphenyl, 3-dimethylamino-4-methylphenyl,2-naphthyl, thien-2-yl, 5-isopropylthien-2-yl, 4-pyridyl,4-tert-butylcyclohexyl, piperdin-4-yl, or 4-tert-butylpiperidin-1-yl; R²is H or methyl; R⁴ is H; R⁵ is H or D-valyloxymethyl; R^(3g) is fluoroor methyl; p is an integer of 1 or 2; and m is an integer of 0, 1, or 2.50. The compound of claim 1 or 12, wherein the compound is:2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-1;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideI-3;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamideI-4;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-6;2-(4-dimethylaminophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-7;2-phenyl-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-8;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(thiophen-2-yl)-2-oxoacetamideI-9;2-(4-methoxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-11;2-(4-cyclopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-12;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-13;2-(4-isopropylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-14;2-(4-(sec-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-15;2-(4-hydroxyphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-16;2-(4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-17;2-(4-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-18;2-(3-tert-butylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-19;2-(4-acetamidophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-20;2-([1,1′-biphenyl]-4-yl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-21;2-(4-fluorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-22;2-(4-trifluoromethylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-23;2-(3,4-dichlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-24;2-(4-((dimethylamino)methyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-25;2-(4-(morpholinomethyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-26;2-(3-methyl-4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-27;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-methylpiperidin-4-yl)phenyl)-2-oxoacetamideI-31;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxo-2-(4-(1,1,1-trifluoropropan-2-yl)phenyl)acetamideI-36;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-40;2-(4-(tert-butyl)phenyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)-2-oxoacetamideI-41;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-methylcyclopropyl)phenyl)-2-oxoacetamideI-42;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(1-hydroxy-2-methylpropan-2-yl)phenyl)-2-oxoacetamideI-43;2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-oxoacetamideI-44;N¹-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-N²,N²-dimethyloxalamideI-70;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-2;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideI-5;(S)-2-(4-(tert-butyl)phenyl)-N-((2-(2,7-dioxoazepan-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-10;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)methyl)-2-oxoacetamideI-32;2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-33;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-N-methyl-2-oxoacetamideI-34;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamideI-37;N-(2-(2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideI-52;2-(3-chloro-4-methylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-53;2-(3-methyl-4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-55;N-((2-(2,6-dioxopiperidin-3-yl)-4-methyl-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideI-60;2-(4-(tert-butyl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-62;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-3-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)propanamideI-63;2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-68;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-phenylacetamideI-83;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6-trimethoxyphenyl)acetamideI-84;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2,4,6-trimethylphenyl)acetamideI-85;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(2-fluorophenyl)acetamideI-86;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(4-trifluoromethylphenyl)acetamideI-87;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(4-methoxyphenyl)-2-oxoacetamideI-89;2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-90;2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-91;2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-93;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-methoxyphenyl)-2-oxoacetamideI-95;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(naphthalen-2-yl)-2-oxoacetamideI-97;2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-99;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(3-fluorophenyl)-2-oxoacetamideI-100;2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-102;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2-(pyridin-4-yl)acetamideI-103;2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxoacetamideI-104;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-28;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-29;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideI-30;2-(3-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-46;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-N-methyl-2-oxoacetamideI-47;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-2-oxoacetamideI-48;(2R)-(3-(4-((2-(4-(tert-butyl)phenyl)-2-oxoacetamido)methyl)-1-oxoisoindolin-2-yl)-2,6-dioxopiperidin-1-yl)methyl2-amino-3-methylbutanoate I-49;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5-fluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-50;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-5,6-difluoro-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-51;2-(3-methyl-4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-54;2-(4-(tert-butyl)phenyl)-N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-oxoacetamideI-56;N-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideI-57;N-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideI-58;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-(5-isopropylthiophen-2-yl)-2-oxoacetamideI-59;2-(4-(tert-butyl)piperidin-1-yl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-61;(2,6-dioxo-3-(1-oxo-4-((2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)-phenyl)acetamido)methyl)isoindolin-2-yl)piperidin-1-yl)methylD-valinate I-64;N-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)ethyl)-2-oxo-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideI-65;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(piperidin-4-yl)phenyl)acetamideI-66;2-(4-(tert-butyl)cyclohexyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-67;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(p-tolyl)acetamide1-72;2-(3,4-difluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-73;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-phenylacetamideI-74;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxo-2-(4-(trifluoromethyl)phenyl)acetamideI-75;2-(4-cyanophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-76;2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-77;2-(4-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-78;2-(2,4,6-trimethoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-79;2-(2,4,6-trimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-80;2-(4-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-81;2-(2-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-82;2-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-88;2-(3-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-92;2-(3-methoxyphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-94;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-(naphthalen-2-yl)-2-oxoacetamideI-96;2-(3,5-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-98;2-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-101;2-(4-(tert-butyl)-2,6-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-105;2-(4-bromophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-106;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamideI-35;2-(4-(tert-butyl)phenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-4-yl)methyl)-2-oxoacetamideI-38;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)-2-oxoacetamideI-39;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxoacetamideI-45;N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-oxo-4-phenylbutanamideI-69;N¹-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-N²,N²-dimethyloxalamideI-71; or an enantiomer, a mixture of enantiomers, a diastereomer, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 51. The compoundof claim 22, wherein the compound is:N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamideII-18;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamideII-28;(S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamideII-29;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2,2-difluoroacetamideII-38;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamideII-129;N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideII-164; orN-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideII-165; or an enantiomer, a mixture of enantiomers, a diastereomer, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 52. The compoundof claim 23, wherein the compound is(E)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-(1-(trifluoromethyl)cyclopropyl)-phenyl)acrylamideII-149; or an enantiomer, a mixture of enantiomers, a diastereomer, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 53. A compound ofFormula (IIa), (IIb), or (IIc):

or a pharmaceutically acceptable salt thereof, wherein: each n isindependently an integer of 0, 1, or 2; one of R¹ and R² is selectedfrom the group consisting of H, deuterium, hydroxyl, halogen, cyano,nitro, optionally substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy,—(CH₂)_(t)—NR^(7a)R^(8a), —O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b),—S(O)₂NR^(7c)R^(8c), —OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a),—NR^(7d)C(O)R^(11b), —S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl, optionally substitutedC₃-C₈ carbocyclyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted 3 to 10 membered heterocyclyl, and optionally substituted 5to 10 membered heteroaryl; and the other of R¹ and R² is

each R³ is independently H, deuterium, C₁-C₆ alkyl,

each R⁴ is independently H, deuterium, halogen, or optionallysubstituted C₁-C₆ alkyl; L is

Z¹ is C(═O), C(═NH), S(O)₂ or (CH₂)_(k); Z² is a bond, S, O, or NH; Z³is C(═O) or S(O)₂; ring A is C₆-C₁₀ aryl, 5 to 10 membered heteroaryl,C₃-C₈ carbocyclyl, or 3 to 10 membered heterocyclyl, each optionallysubstituted with one or more R^(A); each of R^(a1), R^(a2), and R^(a3)is independently H, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₆-C₁₀ aryl, optionally substituted C₇-C₁₄ aralkyl, oroptionally substituted C₃-C₈ carbocyclyl; each R^(b1), R^(b2), R^(c1),and R^(c2) is independently H, hydroxyl, substituted or unsubstitutedamino, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, or C₃-C₈ carbocyclyl; or R^(b1) and R^(c1) together with thecarbon atom to which they are attached form a C₃-C₈ carbocyclyl; orR^(b2) and R^(c2) together with the carbon atom to which they areattached form a C₃-C₈ carbocyclyl; wherein each C₃-C₈ carbocyclyl isoptionally substituted with one or more R^(B); each R^(5a), R^(5b),R^(10a), and R^(10b) is independently H, optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆ alkenyl, optionally substitutedC₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl, optionallysubstituted 5 to 10 membered heteroaryl, optionally substituted C₇-C₁₄aralkyl, optionally substituted 3 to 10 membered heterocyclyl, oroptionally substituted C₃-C₈ carbocyclyl; each of R^(6a) and R^(6b) isindependently H, halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl,C₁-C₆ haloalkoxy, or C₃-C₈ carbocyclyl; each R^(7a), R^(7b), R^(7c),R^(7d), R^(7e), R^(8a), R^(8b), R^(8c), R⁷, and R⁸ is independently H,optionally substituted C₁-C₆ alkyl, optionally substituted C₆-C₁₀ aryl,optionally substituted C₇-C₁₄ aralkyl, or optionally substituted C₃-C₈carbocyclyl; or R^(7a) and R^(8a) together with the nitrogen atom towhich they are attached form optionally substituted 3 to 7 memberedheterocyclyl; or R^(7b) and R^(8b) together with the nitrogen atom towhich they are attached form optionally substituted 3 to 7 memberedheterocyclyl; or R^(7c) and R^(8c) together with the nitrogen atom towhich they are attached form optionally substituted 3 to 7 memberedheterocyclyl; wherein each of C₆-C₁₀ aryl, C₇-C₁₄ aralkyl, C₃-C₈carbocyclyl, or 3 to 7 membered heterocyclyl is optionally substitutedwith one or more R^(B); each R⁹ is independently optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(11a),R^(11b), R^(11c), and R^(11d) is independently optionally substitutedC₁-C₆ alkyl, optionally substituted C₂-C₆ alkenyl, optionallysubstituted C₂-C₆ alkynyl, optionally substituted C₆-C₁₀ aryl,optionally substituted 5 to 10 membered heteroaryl, optionallysubstituted C₇-C₁₄ aralkyl, optionally substituted 3 to 10 memberedheterocyclyl, or optionally substituted C₃-C₈ carbocyclyl; each R^(A) isindependently halogen, cyano, nitro, hydroxyl, optionally substitutedC₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆haloalkyl, C₁-C₆ haloalkoxy, —(CH₂)_(t)—NR^(7a)R^(8a),—O(CH₂)_(t)—NR^(7a)R^(8a), —C(O)NR^(7b)R^(8b), —S(O)₂NR^(7c)R^(8c),—OR⁹, —SR^(10a), —C(O)OR^(10b), —C(O)R^(11a), —NR^(7d)C(O)R^(11b),—S(O)₂R^(11c), —NR^(7e)S(O)₂R^(11d), (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆alkoxy)C₁-C₆ alkyl, phenyl, 5 to 10 membered heteroaryl, C₃-C₈carbocyclyl, or 3 to 10 membered heterocyclyl, wherein each of phenyl, 5to 10 membered heteroaryl, C₃-C₈ carbocyclyl, and 3 to 10 memberedheterocyclyl is optionally substituted with one or more R^(B); eachR^(B) is independently C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆haloalkoxy, (C₁-C₆ alkoxy)C₁-C₆ alkyl, —O(C₁-C₆ alkoxy)C₁-C₆ alkyl,halogen, or cyano; or two geminal R^(B) form oxo; m1, m2, m3, and m4 areeach independently an integer of 0, 1, 2, 3, 4 or 5; k is an integer of1, 2, 3, 4, 5 or 6; and each t is independently an integer of 0, 1, 2,3, 4, or 5; provided that: when, in Formula (IIa), one of R¹ or R² is H,n is 1 or 2, R³ is H, R⁴ is H, L is —CH₂—NH—C(═O)—NH—CH₂— or—CH₂—NH—C(═O)—NH—*, then ring A is not 3-chloro-4-methylphenyl, whereinthe symbol “*” indicates the attachment point to ring A; when, inFormula (IIb), R¹ is H, n is 1 or 2, R³ is H, R⁴ is H, L is—NH—C(═O)—CH₂—*, —CH₂—NH—C(═O)—CH₂—*, or —CH₂—NH—C(═S)—NH—*, then ring Ais not 3-chloro-4-methylphenyl, wherein the symbol “*” indicates theattachment point to ring A; when, in Formula (IIb), R¹ is H, n is 1 or2, R³ is H, R⁴ is H, L is —NH—C(═O)—NH—, —CH₂—NH—C(═O)—NH—CH₂—, or—CH₂—NH—C(═O)—NH—*, then ring A is not any of 3-chloro-4-methylphenyl,4-methyl-3-isopropylphenyl, 3-chloro-4-methyl-5-isopropylpheny,3-chloro-4,6-dimethylphenyl, 4-methyl-3-trifluoromethylphenyl,3-chloro-4-trifluoromethylphenyl, 6-chloro-5-methylpyrid-2-yl, and2-methylpyrid-5-yl, wherein the symbol “*” indicates the attachmentpoint to ring A; and when, in Formula (IIc), R¹ is H, n is 1, R³ is H,R⁴ is H, L is —CH₂—NH—C(═O)—NH—*, then ring A is not3-chloro-4-methylphenyl, wherein the symbol “*” indicates the attachmentpoint to ring A.
 54. The compound of claim 53, having the structure ofFormula (IIa), wherein R² is H.
 55. The compound of claim 53, having thestructure of Formula (IIb), wherein R¹ is H.
 56. The compound of any oneof claims 53 to 55, wherein n is an integer of
 1. 57. The compound ofany one of claims 53 to 56, wherein R³ is H or C₁-C₆ alkyl.
 58. Thecompound of claim 57, wherein R³ is H.
 59. The compound of any one ofclaims 53 to 57, wherein R³ is

and wherein R^(5a) and R^(Sb) are each independently C₁-C₆ alkyl. 60.The compound of any one of claims 53 to 57, wherein R³ is

wherein R⁷ and R⁸ are each H, and R^(6a) and R^(6b) are eachindependently H or optionally substituted C₁-C₆ alkyl.
 61. The compoundof any one of claims 53 to 60, wherein R⁴ is H or C₁-C₆ alkyl.
 62. Thecompound of claim 61, wherein R⁴ is H or C₁-C₆ alkyl.
 63. The compoundof any one of claims 53 to 62, wherein L is

wherein each R^(a1) and R^(a2) is independently H or C₁-C₆ alkyl, andwherein Z² is a bond or O.
 64. The compound of claim 63, wherein L is


65. The compound of claim 63 or 64, wherein each m1 is independently 0,1, or
 2. 66. The compound of any one of claims 63 to 65, wherein each m2is independently 0, 1, 2, or
 3. 67. The compound of any one of claims 53to 66, wherein L is

m1 is 0, and m2 is
 1. 68. The compound of any one of claims 53 to 66,wherein L is

and wherein R^(a3) is H or C₁-C₆ alkyl.
 69. The compound of claim 68,wherein L is


70. The compound of claim 68 or 69, wherein each m3 is independently 0,1 or
 2. 71. The compound of any one of claims 68 to 70, wherein each m4is independently 1, 2 or
 3. 72. The compound of any one of claims 68 to71, wherein both R^(b2) and R^(c2) are H.
 73. The compound of any one ofclaims 68 to 72, wherein one of R^(b2) and R^(c2) is H, halogen, C₁-C₆alkyl, or C₁-C₆ haloalkyl and the other one of R^(b2) and R^(c2) ishalogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, —NH₂, —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)₂, or hydroxyl.
 74. The compound of claim 73,wherein R^(b2) is H and R^(c2) is hydroxyl, trifluoromethyl, methyl,ethyl, isopropyl, cyclopropyl, methoxy, —NH₂, —NHCH₃, —NHC₂H₅, —N(CH₃)₂,or —N(C₂H₅)₂.
 75. The compound of claim 73, wherein R^(b2) is fluoro ortrifluoromethyl, and R^(c2) is fluoro or hydroxyl.
 76. The compound ofany one of claims 68 to 75, wherein R^(b2) and R^(c2) together with thecarbon atom to which they are attached form a C₃-C₇ cycloalkyloptionally substituted with one or more R^(B).
 77. The compound of anyone of claims 53 to 76, wherein ring A is phenyl, unsubstituted orsubstituted with one or more R^(A).
 78. The compound of any one ofclaims 53 to 76, wherein ring A is selected from the group consisting ofpyridyl, thienyl, furyl, pyrimidinyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, and thiadiazolyl, each independentlyunsubstituted or substituted with one or more R^(A).
 79. The compound ofany one of claims 53 to 76, wherein ring A is phenyl, naphthyl, thienyl,pyridyl, piperidinyl, or cyclohexyl, each of which is optionallysubstituted with one, two, or three substituents R^(A), wherein eachsubstituent R^(A) is independently cyano, fluoro, chloro, bromo, methyl,trifluoromethyl-ethyl, trifluoromethyl, dimethylaminomethyl,morpholinylmethyl, isopropyl, sec-butyl, tert-butyl,hydroxyl-tert-butyl, cyclopropyl, methylcyclopropyl,trifluoromethyl-cyclopropyl, phenyl, methyl-piperidinyl, hydroxyl,methoxy, dimethylamino, or acetamido.
 80. The compound of any one ofclaims 53 to 76, wherein ring A is phenyl, cyanophenyl, fluorophenyl,chlorophenyl, bromophenyl, methylphenyl, (1-trifluoromethylethyl)phenyl,trifluoromethylphenyl, dimethylaminomethylphenyl,morpholin-4-ylmethylphenyl, isopropylphenyl, sec-butylphenyl,tert-butylphenyl, (hydroxyl-tert-butyl)phenyl, cyclopropylphenyl,(1-methylcyclopropyl)-phenyl, (1-trifluoromethylcyclopropyl)-phenyl,phenylphenyl, (1-methylpiperidin-4-yl)phenyl, hydroxylphenyl,methoxyphenyl, dimethylaminophenyl, acetamidophenyl, difluorophenyl,dichlorophenyl, chloro-methylphenyl, methyl-tert-butylphenyl,dimethylphenyl, trimethylphenyl, trimethoxyphenyl,dimethyl-tert-butylphenyl, dimethylamino-methylphenyl, naphthyl,thienyl, isopropylthienyl, pyridyl, tert-butylcyclohexyl, piperidinyl,or tert-butylpiperidinyl.
 81. The compound of any one of claims 53 to76, wherein ring A is phenyl, 4-cyanophenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,4-bromophenyl, 4-methylphenyl, 4-(1-trifluoromethylethyl)-phenyl,4-trifluoromethylphenyl, 4-dimethylaminomethylphenyl,4-morpholin-4-ylmethylphenyl, 4-isopropylphenyl, 4-sec-butylphenyl,3-tert-butylphenyl, 4-tert-butylphenyl, 4-(hydroxyl-tert-butyl)phenyl,4-cyclopropylphenyl, 4-(1-methyl-cyclopropyl)phenyl,4-(1-trifluoromethylcyclopropyl)phenyl, 4-phenylphenyl,4-(1-methylpiperidin-4-yl)phenyl, 4-hydroxylphenyl, 3-methoxyphenyl,4-methoxyphenyl, 4-dimethylaminophenyl, 4-acetamidophenyl,3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-methylphenyl,3-methyl-4-tert-butylphenyl, 3,5-dimethylphenyl, 2,4,6-trimethylphenyl,2,4,6-trimethoxyphenyl, 2,6-dimethyl-4-tert-butylphenyl,3-dimethylamino-4-methylphenyl, 2-naphthyl, thien-2-yl,5-isopropylthien-2-yl, 4-pyridyl, 4-tert-butylcyclohexyl, piperdin-4-yl,or 4-tert-butylpiperidin-1-yl.
 82. The compound of claim 53, wherein thecompound is:1-(3-(dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-1;1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)ureaII-2;(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-3;1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-methoxy-4-methylphenyl)ureaII-4;1-(4-chloro-3-(trifluoromethoxy)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-5;1-(3-chloro-4-methoxyphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-6;1-(benzo[d][1,3]dioxol-5-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-7;1-(3-chloro-5-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-8;1-(3,5-bis(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-9;1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-10;1-(3-(dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-11;N-(5-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)-2-methylphenyl)acetamideII-12;1-(3-chloro-4-(dimethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-13;N-(2-chloro-4-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)phenyl)acetamideII-14;1-(3-chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)ureaII-15;5-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)-2-methylbenzamideII-16;(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-17;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-fluorophenyl)acetamideII-18;(S)-1-(3-chloro-4-methylbenzyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-19;1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1,3-dimethylureaII-20;1-(3-chloro-4-methylbenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-21;1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1-methylureaII-22;3-(1-(((3-((3-chloro-4-methylphenyl)amino)propyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dioneII-23;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamideII-24;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-fluorophenyl)acetamideII-25;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methyl-4-morpholinophenyl)ureaII-26;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methyl-4-(pyrrolidin-1-yl)phenyl)ureaII-27;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamideII-28;(S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamideII-29;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)acetamideII-30;1-(3-chloro-4-methylphenyl)-3-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)ureaII-31;1-(3-chloro-4-methylbenzyl)-3-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)ureaII-32;3-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)propenamideII-33;3-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamideII-34;3-{2-[(3-chloro-4-methylphenylsulfonylamino)methyl]-6-oxo-3-thia-7-azabicyclo[3.3.0]octa-1,4-dien-7-yl}-2,6-piperidinedioneII-35;1-(2,6-dichlorobenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)urII-36;1-(2,6-dichlorobenzyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-37;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2,2-difluoroacetamideII-38;1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)thioureaII-39;1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(5-methyl-4-(trifluoromethyl)pyrimidin-2-yl)ureaII-40;4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamideII-41;1-(2,6-dichlorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-42;1-(2,6-dichlorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-43;3-{3-[(3-chloro-4-methylphenylsulfonylamino)methyl]-8-oxo-2-thia-7-azabicyclo[3.3.0]octa-1(5),3-dien-7-yl}-2,6-piperidinedioneII-44;1-(3-(dimethylamino)-4-fluorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-45;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-hydroxy-4-methylphenyl)ureaII-46;1-(3-(diethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-47;1-(3-(dimethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-48;1-(3-(dimethylamino)-5-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-49;1-(3-(dimethylamino)-5-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-50;1-(3-((dimethylamino)methyl)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-51;1-(4-(diethylamino)-3-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-52;1-(3-((dimethylamino)methyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-53;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-isopropyl-4-methylphenyl)ureaII-54;1-(3-(dimethylamino)-4-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-55;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(isopropyl(methyl)amino)phenyl)ureaII-56;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-3-yl)methyl)acetamideII-57;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-methoxy-4-methylphenyl)ureaII-58;1-(4-(dimethylamino)-3-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-59;1-(3-(dimethylamino)-5-isopropylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-60;2-(4-(dimethylamino)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamideII-61;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamideII-62;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(3-isopropyl-4-methoxyphenyl)acetamideII-63;3-(1-(((54(3-chloro-4-methylphenyl)amino)pentyl)amino)methyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dioneII-64;3-(2-(((3-((3-chloro-4-methylphenyl)amino)propyl)amino)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dioneII-65;3-(2-(((3-((3-chloro-4-methylphenyl)amino)propyl)amino)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)piperidine-2,6-dioneII-66;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamideII-67;2-(3-(dimethylamino)-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamideII-68;1-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)methanesulfonamideII-69;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-isopropylphenyl)ureaII-70;1-(3-(diethylamino)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-71;1-(3-chloro-4-methylphenyl)-3-((5-(2,5-dioxopyrrolidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-72;1-(3-chloro-4-methylphenyl)-3-((5-(3-methyl-2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-73;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-isopropylphenyl)acetamideII-74;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-methylcyclohexyl)acetamideII-75;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(3-(piperidin-1-yl)phenyl)acetamideII-76;2-(3-(2-(dimethylamino)ethoxy)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamideII-77;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-morpholinoacetamideII-78;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)acetamideII-79;2-(4-(2-(dimethylamino)ethoxy)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamideII-80;(3-(24(3-(3-(dimethylamino)-4-methylphenyl)ureido)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methylD-valinate II-81;(3-(24(3-(3-chloro-4-methylphenyl)ureido)methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methylD-valinate II-82;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-morpholinophenyl)acetamideII-83;4-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamideII-84;4-(4-(dimethylamino)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamideII-85;4-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-methylbutanamideII-86;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamideII-87;2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(p-tolyl)acetamideII-88;2-amino-2-(3-chlorophenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)acetamideII-89;(S)-1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-90;(R)-1-(3-chloro-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-91;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamideII-92;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-(pyrrolidin-1-yl)phenyl)acetamideII-93;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-methylbutanamideII-94;2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-methylbutanamideII-95;1-(3-(dimethylamino)-4-ethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-96;1-(3-(diethylamino)-4-fluorophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-97;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(4-methyl-3-(pyrrolidin-1-yl)phenyl)ureaII-98;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(pyrrolidin-1-yl)phenyl)ureaII-99;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(3-(ethyl(methyl)amino)-4-methylphenyl)ureaII-100;4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-methylbutanamideII-101;(2S)-2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamideII-102;(2R)-2-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)propenamideII-103;(S)-4-(3-chloro-4-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-dimethylbutanamideII-104; di-tert-butyl((3-(2-((3-(3-(dimethylamino)-4-methylphenyl)ureido)-methyl)-6-oxo-4,6-dihydro-5H-thieno[2,3-c]pyrrol-5-yl)-2,6-dioxopiperidin-1-yl)methyl)phosphate II-105;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-isopropylphenyl)-3-methylbutanamideII-106;N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(perfluorophenyl)acetamideII-107;2-(dimethylamino)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(2-fluorophenyl)acetamideII-108;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-phenylbutanamideII-109;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-phenylthioureaII-110;1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(4-(trifluoromethoxy)phenyl)thiouII-111;2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-propoxyphenyl)acetamideII-112;2-amino-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-(4-hydroxyphenyl)acetamideII-113;1-(3-(dimethylamino)-4-methylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4,6-dioxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-114;4-(4-(dimethylamino)-3-methylphenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)butanamideII-115;N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(3-fluoro-2-methoxyphenyl)acetamideII-116;4-bromo-2,5-dichloro-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiophene-3-sulfonamideII-117; methyl5-chloro-3-(N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)sulfamoyl)thiophene-2-carboxylateII-118;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-methyl-1,2,3-thiadiazole-5-carboxamideII-119;N-(5-(N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)sulfamoyl)-4-methylthiazol-2-yl)acetamideII-120;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,3,4,5,6-pentafluorobenzenesulfonamideII-121;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamideII-122;1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(2,3,5,6-tetrachlorophenyl)thioureaII-123;4-(tert-butyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)benzenesulfonamideII-124; methyl3-(3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureido)thiophene-2-carboxylateII-125;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)thiazole-2-carboxamideII-126;1-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)cyclopropane-1-carboxamideII-127;1-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)methanesulfonamideII-128;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoroacetamideII-129;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)furan-3-sulfonamideII-130;4-(tert-butyl)-N-(2-(5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)ethyl)benzenesulfonamideII-131;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2-hydroxyacetamideII-132;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3,3,3-trifluoro-2-hydroxypropanamideII-133;3-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)furan-2-carboxamideII-134;4-bromo-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(trifluoromethoxy)benzenesulfonamideII-135;2-chloro-N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)thiazole-5-carboxamideII-136; methyl2-(3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureido)thiophene-3-carboxylateII-137;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(6-morpholinopyridin-3-yl)ureaII-138;1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-139;N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3,5-dimethylisoxazole-4-carboxamideII-140;N-(5-(N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)sulfamoyl)-4-methylthiazol-2-yl)acetamideII-141;N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2,5-dimethylfuran-3-sulfonamideII-142;5-(N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)sulfamoyl)-2-methoxy-N,N-dimethylbenzamideII-143;N-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-2-(propylthio)nicotinamideII-144;1-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3-(3-phenoxypropyl)ureaII-145;N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-4-(4-morpholinophenyl)butanamideII-146;2-(4-(tert-butyl)phenyl)-N-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-3,3,3-trifluoropropanamideII-147;1-(4-(tert-butyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)ureaII-148;1-(2,3-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-150;1-(2,4-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-151;1-(2,5-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-152;1-([1,1′-biphenyl]-4-yl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-153;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(4-methoxyphenyl)ureaII-154;1-(4-cyanophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-155;1-(2,6-dimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-155;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-phenethylthioureaII-157;1-(2-trifluoromethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-158;1-(3-cyanophenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-159;1-(4-chloro-2-trifluoromethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-160;1-(2,4,6-trimethylphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-161;1-(3,5-dimethoxyphenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)ureaII-162;1-((5-(2,6-dioxopiperidin-3-yl)-6-oxo-5,6-dihydro-4H-thieno[2,3-c]pyrrol-2-yl)methyl)-3-(naphthalen-1-yl)ureaII-163; orN-((5-(2,6-Dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)-2,2-difluoro-2-(4-(1-(trifluoromethyl)cyclopropyl)phenyl)acetamideII-165; or an enantiomer, a mixture of enantiomers, a diastereomer, amixture of two or more diastereomers, a tautomer, a mixture of two ormore tautomers, or an isotopic variant thereof; or a pharmaceuticallyacceptable salt, solvate, hydrate, or prodrug thereof.
 83. Apharmaceutical composition comprising a compound of any one of claims 1to 82 or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.
 84. A method of treating,ameliorating, or preventing a disease, disorder, or condition associatedwith a protein in a subject, comprising administering a therapeuticallyeffective amount of a compound of any one of claims 1 to 82, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition of claim 83; wherein the protein is a cytokine, aiolos,ikaros, helios, CK1α, or GSPT1.
 85. The method of claim 84, wherein theprotein is a cytokine.
 86. The method of claim 84 or 85, wherein thecytokine is IL-1β, IL-6, TNFα, and IL-2.
 87. The method of any one ofclaims 84 to 86, wherein the disease, disorder, or condition isinflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis,ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatorybowel diseases, Crohn's disease, ulcerative colitis, uveitis,inflammatory lung diseases, chronic obstructive pulmonary disease,Alzheimer's disease, or cancer.
 88. The method of claim 87, wherein thedisease, disorder, or condition is cancer.
 89. The method of claim 88,wherein the cancer is breast cancer, melanoma, renal cancer, prostatecancer, colon cancer, lung cancer, bladder cancer, brain cancer,cervical cancer, head and neck cancer, esophageal and gastric cancers,osteosarcoma, multiple myeloma, leukemia, lymphoma, neuroendocrinecancer, hepatocellular carcinoma, renal cell cancer, pancreatic cancer,thyroid cancer, glioblastoma, ovarian, endometrial cancer, orastrogliosis.
 90. The method of any one of claims 84 to 89, wherein thesubject is a human.
 91. A method of modulating a protein activity in acell, comprising contacting the cell with an effective amount of acompound of any one of claims 1 to 82, or a pharmaceutically acceptablesalt thereof, wherein the protein is a cytokine, aiolos, ikaros, helios,CK1α, or GSPT1.
 92. The method of claim 91, wherein the method is toinhibit the protein activity.
 93. The method of claim 91 or 92, whereinthe cytokine is IL-1β, IL-6, TNFα, or IL-2.